Malignant Tumors of Bone

Osteosarcoma

Osteosarcoma is a tumor characterized by the production of osteoid by malignant cells. It is the most common nonhematologic primary malignancy of bone. The incidence is 1:3 per 1 million per year. Onset can occur at any age; however, primary high-grade osteosarcoma occurs most commonly in the second decade of life. Parosteal osteosarcoma has a peak incidence in the third and fourth decades, and secondary osteosarcomas (e.g., those that occur in the setting of Paget disease or previous radiation therapy) are more common in older individuals. The incidence is slightly higher in males (with the exception of parosteal osteosarcoma, which is more common in females). There are no significant differences among races, and genetic factors rarely have been shown to play a role, although osteosarcoma may be more common in patients with the hereditary form of retinoblastoma, Rothmund-Thomson syndrome, and Li-Fraumeni syndrome. All skeletal locations can be affected; however, most primary osteosarcomas occur at the sites of the most rapid bone growth, including the distal femur, the proximal tibia, and the proximal humerus.

Almost all patients with high-grade osteosarcoma report progressive pain (patients with low-grade surface osteosarcomas may report a painless mass). Pain initially may improve with conservative measures and activity modifications, which can lead to a false sense of security for the patient and the physician. The pain eventually becomes severe if the diagnosis is delayed. Night pain may be an important clue to the true diagnosis; however, only about 25% of patients experience this phenomenon. Patients frequently are misdiagnosed with a more common musculoskeletal problem at the initial visit. The average delay from the onset of symptoms to the correct diagnosis was approximately 15 weeks in one study. This included the sum of the average patient delay of 6 weeks (the time between the onset of symptoms and initial physician encounter) and the average physician delay of 9 weeks (the time from the first visit to the correct diagnosis). The primary reasons for delay on the part of physicians included failure to obtain radiographs at the initial visit and, more important, failure to repeat the radiographs when a patient’s symptoms persisted or worsened.

Although the radiographic appearance of osteosarcoma can vary, plain radiographs are the most valuable tools for making the correct diagnosis. The most common appearance is that of an aggressive lesion in the metaphysis of a long bone. Approximately 10% are primarily diaphyseal, and less than 1% are primarily epiphyseal. Although the lesion can be either predominantly blastic or predominantly lytic, more commonly areas of bone production and bone destruction are present. The lesion usually is quite permeative, and the borders are ill defined. If the tumor has broken through the cortex, a soft-tissue mass may be present at the time of diagnosis. Periosteal reaction may take the form of a “Codman triangle,” or it may have a “sunburst” or “hair-on-end” appearance. Magnetic resonance imaging (MRI) is the best imaging modality to measure the extent of the tumor within the bone and in the soft tissue and to determine the relationship of the tumor to nearby anatomic structures. A bone scan should be obtained to look for skeletal metastases, and radiography and computed tomography (CT) of the chest should be done to search for pulmonary metastases; the lungs are the most common sites of metastases. These tests should be done before biopsy.

Osteosarcomas are categorized as primary or secondary. Primary osteosarcomas are subcategorized as conventional osteosarcoma, low-grade intramedullary osteosarcoma, parosteal osteosarcoma, periosteal osteosarcoma, high-grade surface osteosarcoma, telangiectatic osteosarcoma, and small cell osteosarcoma.

Most osteosarcomas are classified as conventional osteosarcomas ( Figs. 27.1 to 27.3 ) and have a radiographic appearance as previously described. These high-grade tumors begin in an intramedullary location but may break through the cortex and form a soft-tissue mass. Histologically, they may be primarily osteoblastic, fibroblastic, or chondroblastic; however, to establish the diagnosis, osteoid production from the tumor cells must be shown. The spindle cell component is high grade with hypercellularity, abundant mitotic figures, and marked nuclear pleomorphism.

Periosteal osteosarcoma ( Fig. 27.4 ) is an intermediate-grade malignancy that arises on the surface of the bone. The most common locations are the diaphyses of the femur and tibia. It occurs in a slightly older and broader age group. Histological examination of periosteal osteosarcoma shows strands of osteoid-producing spindle cells radiating between lobules of cartilage.

Low-grade intramedullary osteosarcoma is a rare type characterized by an indolent course with relatively benign features on radiograph. In some patients, it can be mistaken radiographically and histologically for an osteoblastoma or fibrous dysplasia. As the name implies, it is located in an intramedullary location. If left untreated, it may erode through the cortex very late in the disease process. Microscopically, it consists of slightly atypical spindle cells producing slightly irregular osseous trabeculae.

Parosteal osteosarcoma ( Fig. 27.5 ) is also a rare, low-grade malignancy, but it arises on the surface of the bone and invades the medullary cavity only at a late stage. It has a peculiar tendency to occur as a lobulated ossified mass on the posterior aspect of the distal femur. CT may be helpful in differentiating this subtype of osteosarcoma from myositis ossificans or an osteochondroma. The ossification in myositis ossificans is more mature at the periphery of the lesion, whereas the center of a parosteal osteosarcoma is more heavily ossified. Parosteal osteosarcoma can be easily differentiated from an osteochondroma because the CT scan of an osteochondroma shows a medullary cavity containing marrow in continuity with the medullary canal of the involved bone. Microscopically, similar to a low-grade intramedullary osteosarcoma, parosteal osteosarcoma consists of slightly atypical spindle cells producing slightly irregular osseous trabeculae.

High-grade surface osteosarcoma is the least common type of osteosarcoma. As the name implies, it is an aggressive tumor arising on the outer aspect of the cortex. Radiographs show an invasive lesion with ill-defined borders. Similar to conventional osteosarcoma, the microscopic appearance is that of a high-grade tumor with hypercellularity, mitotic figures, and marked nuclear pleomorphism. In contrast to parosteal osteosarcoma, medullary involvement is common at the time of diagnosis.

Telangiectatic osteosarcoma is a purely lytic lesion. On a radiograph, it can have an invasive appearance, or it can have a ballooned appearance similar to that of an aneurysmal bone cyst. Grossly, it resembles a blood-filled cyst with only a very small solid portion. Microscopically, on low power, it most commonly resembles an aneurysmal bone cyst with blood-filled spaces separated by thin septa. On higher power magnification, however, the cells in the septa appear frankly malignant.

Small cell osteosarcoma, another rare variant, is a high-grade lesion that consists of small blue cells and may resemble Ewing sarcoma or lymphoma. If present in only a small quantity, the osteoid can be difficult to differentiate from the fibrin-like material that may be present in Ewing sarcoma. Cytogenetic and immunohistochemistry studies sometimes are needed to differentiate these lesions.

Secondary osteosarcomas occur at the site of another disease process. They rarely occur in young patients but constitute almost half of the osteosarcomas in patients older than 50 years. The most common factors associated with secondary osteosarcomas include Paget disease and previous radiation therapy. The incidence of osteosarcoma in Paget disease is approximately 1% and may be higher (5% to 10%) for patients with advanced polyostotic disease. Paget osteosarcoma most commonly occurs in patients in the sixth to eighth decades of life, and the pelvis is the most common location. Radiation-associated osteosarcoma occurs in approximately 1% of patients who have been treated with greater than 2500 cGy and can occur in unusual locations, such as the skull, spine, clavicle, ribs, scapula, and pelvis ( Fig. 27.6 ) . Although osteosarcoma is the most common radiation-associated sarcoma, fibrosarcoma and malignant fibrous histiocytoma (MFH) are also relatively common in this setting. The time to onset of the secondary osteosarcoma averages 10 to 15 years after radiation exposure but may occur 3 years to several decades after treatment. Other conditions that have been reported to be associated with secondary osteosarcomas include fibrous dysplasia, bone infarcts, osteochondromas, chronic osteomyelitis, melorheostosis, and osteogenesis imperfecta; however, secondary osteosarcomas are extremely rare in these settings, and a causal relationship has not been established.

Before the advent of multiple-agent chemotherapy, the prognosis for patients with osteosarcoma was dismal. Despite treatment consisting of wide or radical amputation, approximately 80% of patients died as a result of distant metastases, usually within 2 years. With today’s multiple-agent chemotherapy regimens and appropriate surgical treatment, most series report long-term survival of 60% to 75% for patients with high-grade osteosarcoma without metastases at initial presentation and 90% for those with low-grade lesions.

The most important prognostic factor s at the time of diagnosis are the presence and location of metastases. Approximately 15% of patients with osteosarcoma have detectable pulmonary metastases at the time of diagnosis. As a group, these patients continue to have a poor prognosis, with less than 20% long-term survival. (Patients with one or a few resectable pulmonary metastases at presentation may have greater than 50% long-term survival, whereas patients with many, large, or unresectable pulmonary metastases have an extremely poor prognosis.) Patients with nonpulmonary metastases (e.g., bone metastases) have an even worse prognosis, with less than 5% long-term survival. Patients with “skip” metastases (i.e., a metastasis within the same bone as the primary tumor or across the joint from the primary tumor) have the same poor prognosis as patients with distant metastases.

The next most important prognostic feature is the grade of the lesion. Low-grade lesions rarely metastasize, and patients with low-grade lesions have a marked survival advantage over patients with high-grade lesions. Size of the primary tumor also appears to be of prognostic significance. Although authors differ on the specific criteria for what constitutes a large or a small tumor, most studies confirm that patients with large tumors have a worse prognosis than patients with smaller tumors. Skeletal location is also thought to be important because patients with more proximal tumors do worse than patients with more distal tumors. Size and location are likely interrelated variables, however, because most proximal tumors are larger at the time of diagnosis than most distal tumors. Paget osteosarcomas continue to have a poor prognosis, with less than 15% long-term survival. Radiation-associated osteosarcomas have been regarded as having a poor prognosis; however, this may be due primarily to their frequent occurrence in unusual locations where resection is difficult. Radiation-associated osteosarcomas in the extremities may have the same prognosis as any other high-grade osteosarcoma. Age at diagnosis and gender do not seem to be of prognostic significance.

As stated earlier, historically, patients with high-grade osteosarcoma were treated with immediate wide or radical amputation. Despite this treatment, 80% of patients with apparently isolated disease died of distant metastases. From this, it can be deduced that most patients with high-grade osteosarcoma have nondetectable micrometastases at presentation. The goal of adjuvant or neoadjuvant chemotherapy is to treat these micrometastases. Currently, at most musculoskeletal oncology centers, the treatment of high-grade osteosarcoma consists of neoadjuvant chemotherapy, wide or radical surgery (resection or amputation), and adjuvant chemotherapy. Pulmonary metastases likewise are resected if possible after neoadjuvant chemotherapy. The histologic response of the primary tumor to neoadjuvant chemotherapy has been shown to be a good predictor of long-term survival. Greater than 90% tumor necrosis indicates a very good prognosis. Low-grade osteosarcoma can be treated with wide resection or amputation without chemotherapy.

About 50% of patients with high-grade osteosarcoma have some type of relapse after the initial treatment. About 10% of patients have local recurrence after wide resection or wide amputation. Patients who have a local recurrence have a very poor prognosis and usually are treated with a radical amputation (if cure is the goal) and further chemotherapy. Late pulmonary metastases likewise are treated with surgery and chemotherapy. Poor prognostic factors include rapid relapse after completion of the initial treatment, many (more than eight) pulmonary nodules, large (>3 cm) pulmonary nodules, and unresectable pulmonary nodules. Patients with a few, small, resectable pulmonary nodules that occur late may have as high as a 60% chance of cure with aggressive treatment.

Chondrosarcoma

Chondrosarcoma has an incidence about half that of osteosarcoma. It is the second most common nonhematologic primary malignancy of bone. It occurs over a broad age range, with peaks between 40 and 60 years for primary chondrosarcoma and between 25 and 45 years for secondary chondrosarcoma. Chondrosarcoma can occur in any location; however, most are located in a proximal location such as the pelvis, proximal femur, and proximal humerus. Although chondrosarcomas rarely occur in the hand, they are the most common primary malignancy of bone in this location. Similar to most bone tumors, the incidence is slightly higher among males. Race predilection is not significant.

Clinically, most patients with primary chondrosarcomas report increasing pain. A palpable mass may also be present. Chondrosarcomas frequently are slow growing, and symptoms can be present for several years before a patient seeks medical attention. Pain in the absence of a pathologic fracture can be important in helping to differentiate an enchondroma from a low-grade chondrosarcoma. Frequently, patients are referred for evaluation of an asymptomatic cartilaginous lesion discovered as an incidental finding on a bone scan or radiograph obtained for another reason. (The radiographic abnormality usually is the sole reason the patient is referred to the orthopaedic oncologist.) Although an asymptomatic radiographic abnormality is common in a patient with an enchondroma, the diagnosis of chondrosarcoma would be extremely rare in this circumstance. A chondrosarcoma may occur in the area of a treated “enchondroma.” In this circumstance, the original pathology specimen should be reviewed.

Secondary chondrosarcomas arise at the site of a preexisting benign cartilage lesion. They occur most frequently in the setting of multiple enchondromas and multiple hereditary exostoses. In Ollier disease (multiple enchondromas), the incidence of malignancy (most commonly chondrosarcoma) is approximately 25% by the age of 40 years, and in patients with Maffucci syndrome (multiple enchondromas with soft-tissue hemangiomas), the incidence may be even higher. Although data for osteochondromas are difficult to analyze, the lifetime incidence of secondary chondrosarcoma is estimated to be 5% for patients with multiple hereditary exostoses and approximately 1% for patients with solitary osteochondromas ( Fig. 27.7 ). As discussed in Chapter 25 , the true incidence of malignant degeneration of osteochondromas is unknown. Published estimates are likely too high, owing to the effect of referral bias on pathology data at tertiary referral centers. The true prevalence of osteochondromas in the general population is unknown. Whether or not a solitary benign enchondroma has the potential to give rise to a secondary chondrosarcoma is difficult to determine. If this does occur, the incidence is not high enough to warrant prophylactic treatment of asymptomatic enchondromas. Other conditions that have been reported to be associated with secondary chondrosarcoma include synovial chondromatosis, chondromyxoid fibroma, periosteal chondroma, chondroblastoma, previous radiation treatment, and fibrous dysplasia.

The radiographic appearance of chondrosarcoma frequently is diagnostic ( Fig. 27.8 ). Similar to enchondroma, it is a lesion arising in the medullary cavity with irregular matrix calcification. The pattern of calcification has been described as “punctate,” “popcorn,” or “comma shaped.” Compared with enchondroma, however, chondrosarcoma has a more aggressive appearance with bone destruction, cortical erosions, periosteal reaction, and a soft-tissue mass. CT can be helpful to show endosteal erosions or other evidence of a destructive lesion and to differentiate benign from malignant cartilage lesions. The site of the lesion must also be considered because lesions in the hand (the most common site for an enchondroma and a rare site for a chondrosarcoma) may appear aggressive and still be diagnosed as benign. The same amount of cortical destruction shown in a pelvic or proximal femoral lesion would be diagnostic of a chondrosarcoma. Finally, the size of the cartilaginous cap of an osteochondroma, as evaluated with CT or MRI, is important in evaluating the possibility of a secondary chondrosarcoma. If the cartilaginous cap is larger than 2 cm in a skeletally mature patient, a secondary chondrosarcoma must be considered.

Histologically, conventional chondrosarcomas are composed of malignant cells with abundant cartilaginous matrix. (If malignant osteoid is present even in small amounts, the diagnosis should be chondroblastic osteosarcoma; a tumor with different prognostic and therapeutic implications.) Differentiating a low-grade chondrosarcoma from an enchondroma can be difficult solely from a biopsy specimen. Factors that favor a malignant diagnosis include hypercellularity, plump nuclei, more than occasional binucleate cells, a permeative pattern, and entrapment of bony trabeculae ( Fig. 27.9 ). As much tissue as possible should be obtained from the biopsy of a borderline lesion. Perhaps, in no other circumstance is correlation with the clinical and radiographic findings more important. Lesions in the setting of multiple enchondromas, periosteal chondromas, synovial chondromatosis, and enchondromas of the hand all may appear hypercellular and yet still can be benign. This same appearance in a biopsy specimen taken from a solitary large pelvic lesion with radiographically shown cortical erosions would be diagnostic of a chondrosarcoma.

Less common histologic subtypes of chondrosarcoma include dedifferentiated chondrosarcoma, clear cell chondrosarcoma, and mesenchymal chondrosarcoma. Together, these subtypes constitute less than 20% of all chondrosarcomas. Histologically, dedifferentiated chondrosarcoma consists of a high-grade spindle cell sarcoma (most commonly osteosarcoma followed in frequency by fibrosarcoma and MFH adjacent to an otherwise typical low-grade chondrosarcoma ( Fig. 27.10 ). The radiographic features of a dedifferentiated chondrosarcoma often show a more aggressive radiolucent area juxtaposed on an otherwise typical chondrosarcoma.

Clear cell chondrosarcoma is a low-grade malignancy. As the name implies, it consists of round cells with abundant clear cytoplasm and distinct cytoplasmic borders with a background of cartilaginous matrix. Multinucleated giant cells usually are apparent. Clear cell chondrosarcoma has a strong tendency to arise in an epiphysis (especially the proximal femur). It may have benign radiographic features and can be confused with chondroblastoma or giant cell tumor.

Mesenchymal chondrosarcoma is a high-grade tumor consisting of small, round blue cells with islands of benign-appearing cartilage. The cellular portions often have a hemangiopericytomatous pattern of growth with “staghorn-like” vessels. Radiographically, mesenchymal chondrosarcoma may look similar to a conventional chondrosarcoma ( Fig. 27.11 ) . More frequently, however, it has a nonspecific, aggressive radiographic appearance.

The treatment of low-grade chondrosarcoma is controversial, with many authors reporting excellent results after extended curettage with the use of intraoperative adjuvant treatments. Extended curettage is considered adequate treatment only for low-grade lesions that are confined within the medullary canal. Those with soft-tissue extension should be treated similar to high-grade lesions. The treatment of high-grade chondrosarcoma is wide or radical resection or amputation. Because cartilage is relatively avascular, the cells survive transplantation easily. The local recurrence rate after intraoperative tumor contamination is high. For lesions in an expendable location, primary wide resection without a biopsy may be indicated to decrease the chance of tumor contamination. After wide resection, local recurrence is less than 10% and can be treated with repeat wide resection or wide amputation. Likewise, pulmonary metastases should be treated with surgical resection if possible. Chemotherapy has no role in the treatment of conventional chondrosarcoma but is frequently used for the treatment of dedifferentiated and mesenchymal chondrosarcomas. Radiation therapy likewise has a limited role and is used only as a palliative measure for surgically inaccessible lesions.

The prognosis for patients with chondrosarcoma depends mostly on the size, grade, and location of the lesion. If a high-grade lesion cannot be completely resected with wide or radical margins (usually because of its size or location), local recurrence is likely. Patients with low-grade lesions have been reported to have a greater than 90% 10-year survival rate, whereas patients with high-grade conventional chondrosarcoma are reported to have a 20% to 40% 10-year survival rate. The 5-year survival rate is 10% to 25% for patients with dedifferentiated chondrosarcoma, with most deaths occurring in the first 2 years. Because chondrosarcomas often are slow growing, local recurrences and pulmonary metastases may not be detected until years or decades after the primary procedure. A significant percentage of recurrences show a higher histologic grade than the original tumor. Long-term follow-up with regular imaging of the operative site and the chest is imperative so that treatment can be initiated promptly in the event of a recurrence.

Ewing Sarcoma

Ewing sarcoma is the third most common nonhematologic primary malignancy of bone, but it is the second most common (after osteosarcoma) in patients younger than 30 years and the most common in patients younger than 10 years. The incidence is less than one per 1 million per year. Ewing sarcoma has been reported to occur in a wide age range of patients from infants to the elderly, but most occur in patients aged 5 to 25 years. The most common locations include the metaphyses of long bones (often with extension into the diaphysis) and the flat bones of the shoulder and pelvic girdles ( Figs. 27.12 and 27.13 ). Rarely, it occurs in the spine or in the small bones of the feet or hands. Similar to most sarcomas of bone, there is a slightly higher incidence in males. Ewing sarcoma is exceedingly rare in individuals of African descent. There are no known predisposing factors.

Pain is an almost universal complaint of patients with Ewing sarcoma. Usually, the onset is insidious, and the pain may be of long duration before the patient seeks medical attention. The pain may be only mild and intermittent initially and may respond to initial conservative treatment. The average delay from the onset of symptoms to the diagnosis has been reported to be 34 weeks. The average patient delay in one study was 15 weeks from the onset of symptoms until the first medical appointment, and the average physician delay was 19 weeks from the initial visit to correct diagnosis. These numbers show the importance of radiographs at the initial visit and rechecking them at subsequent visits if the patient continues to have symptoms.

In addition to pain, patients may also have fever, erythema, and swelling, suggesting osteomyelitis. Laboratory studies may reveal an increased white blood cell count, an elevated erythrocyte sedimentation rate, and an elevated C-reactive protein level. To complicate matters further, a needle aspirate of Ewing sarcoma may grossly resemble pus, and the tissue may be sent in its entirety to microbiology and none to pathology. (As a general rule, most biopsy specimens should be sent for culture and pathologic analysis.)

Classically, Ewing sarcoma appears radiographically as a destructive lesion in the diaphysis of a long bone with an “onion skin” periosteal reaction. In reality, Ewing sarcoma more often originates in the metaphysis of a long bone but frequently extends for a considerable distance into the diaphysis. Although “skip” metastases (similar to those that occur in osteosarcoma) are not reported in Ewing sarcoma, it is common for a large portion of the bone (or even the entire bone) to be involved. In flat bones, Ewing sarcoma appears as a nonspecific destructive lesion. Regardless of the location, MRI of the entire bone should be ordered to evaluate the full extent of the lesion, which typically extends beyond the abnormality apparent on plain films. MRI is also useful to evaluate the extent of the soft-tissue mass, which often is very large. All patients should have a baseline radiograph and CT of the chest because the lung is the most common site of metastases. A bone scan should be performed because bone is the second most common site of metastases. At some institutions, a bone marrow aspirate is performed as part of the staging of Ewing sarcoma to rule out diffuse systemic disease. Others have recommended FDG-PET/CT or whole-body MRI for this purpose.

Histologically, Ewing sarcoma consists of small blue cells with very little intercellular matrix. Cytogenetic or immunohistochemical studies often are required to differentiate Ewing sarcoma from other small blue cell tumors. The t(11;22)(q24;q12) is the most common translocation diagnostic of Ewing sarcoma and is present in more than 90% of cases. Other diagnostic translocations, including t(21;22)(q22;q12) and t(7;22)(p22;q12), have also been identified. Immunohistochemical staining for the MIC-2 gene product has been reported to be specific for Ewing sarcoma. In addition, Ewing sarcomas usually are periodic acid–Schiff (PAS) positive (owing to intracellular glycogen) and reticulin negative. This is in contrast to lymphomas, which are PAS negative and reticulin positive. Lymphomas also stain positive for leukocyte common antigen and other T- and B-cell antigens. Embryonal rhabdomyosarcoma stains positive for desmin, myoglobin, and muscle-specific actins. Hemangiopericytomas stain positive for factor VIII, and small cell metastatic carcinomas and melanomas stain positive for cytokeratin.

The worst prognostic factor is the presence of distant metastases. Even with aggressive treatment, patients with metastases have only a 20% to 30% chance of long-term survival. The size of the primary lesion has been shown consistently to be of prognostic significance, although specific parameters have not been firmly established. Location has also been reported to be of prognostic significance, but it is difficult to differentiate the effects of location and size because most proximally located tumors are larger at presentation than distally located tumors. Histologic grade is of no prognostic significance because all Ewing sarcomas are considered high grade. Fever, anemia, and elevation of laboratory values (white blood cell count, erythrocyte sedimentation rate, and lactate dehydrogenase) have been reported to indicate more extensive disease and a worse prognosis. Older age at presentation (with a cutoff around the age of 12 to 15 years) and male gender have also been reported to be associated with a worse prognosis. The specific translocation, t(11;22) versus t(21;22), does not seem to affect the clinical course; however, secondary genetic alterations, such as aberrant TP53 expression, may prove to be important. As with osteosarcoma, histologic response to neoadjuvant chemotherapy has been shown to be prognostically important. Greater than 90% necrosis after preoperative chemotherapy indicates a good prognosis.

The treatment of Ewing sarcoma must include neoadjuvant or adjuvant chemotherapy, or both, to treat distant metastases that may or may not be readily apparent at the initial staging. Before the use of multiple-agent chemotherapy, long-term survival was less than 10%. Today, most centers report long-term survival rates of 60% to 75%.

Local treatment of the primary lesion is more controversial. Ewing sarcoma is radiosensitive, yet some authors report a decreased rate of local recurrence (<10%) and an increased rate of overall survival with wide resection of the primary tumor. These reports are difficult to interpret, however, because large, central, unresectable tumors often are treated with radiation, whereas smaller, more accessible lesions (which inherently have a better prognosis) are more likely to be treated with surgery. At this time, the choice between surgery and radiation for treatment of the primary lesion must be made on an individual basis. Repeat staging studies should be obtained after neoadjuvant chemotherapy. The repeat radiographs often show increased ossification, and repeat MRI often shows a marked decrease in the soft-tissue mass. At this point, if it appears that the lesion can be resected with wide margins with an acceptable functional deficit, surgery should be the treatment of the primary lesion. If wide margins would be difficult to obtain or if the functional deficit resulting from surgery would be unacceptable, radiation of the primary lesion is an acceptable alternative. Radiation can also be used as an adjuvant after a marginal resection or a contaminated wide resection. The treatment plan in each case is most appropriately made after long discussions with the patient and the family. The discussions should include expected function after amputation, limb salvage surgery, or radiation and the inherent short-term and long-term risks involved with each option.

Disease relapse is associated with a poor prognosis despite aggressive treatment of the relapse with further surgery, radiation, and chemotherapy. Patients with local recurrence have been reported to have about a 20% 5-year survival rate, whereas patients who relapse with distant metastases have approximately a 10% 5-year survival rate. As with osteosarcoma, time to relapse has prognostic significance. Patients who relapse within the first year after primary treatment have a worse prognosis than patients who have an extended disease-free interval.

Chordoma

Chordoma is a rare malignant neoplasm that arises from notochord remnants. Chordoma is the second most common primary malignancy in the spine (behind myeloma) and is the most common primary malignancy of the sacrum. Greater than 50% of chordomas arise in the sacrococcygeal area, and more than 30% arise at the base of the skull; the remainder are dispersed throughout the rest of the spine. Peak incidence for sacrococcygeal chordomas occurs in the fifth to seventh decades, whereas the peak for sphenooccipital lesions is the fourth to sixth decades. Most series show a marked male predominance (3:1), especially for sacrococcygeal tumors.

The presenting signs and symptoms vary according to the site of the lesion. Because most chordomas are slow growing, patients frequently have symptoms for more than a year before diagnosis. Patients with tumors in the sphenooccipital region may report headaches or symptoms related to cranial nerve compression. In the spine, symptoms can be caused by nerve root or cord compression. If an anterior mass exists with a cervical spine lesion, the symptoms may be similar to those caused by a retropharyngeal abscess. The most common presenting complaint for patients with sacrococcygeal tumors is low back pain. Bowel and bladder disturbance and sciatic pain are also common with sacral tumors. A palpable mass frequently is present on rectal examination.

Radiographically, chordomas appear as destructive lesions ( Fig. 27.14 ). They virtually always arise from the midline. Sacrococcygeal lesions often are missed on the initial radiographic examination because of overlying bowel gas. They are usually seen more easily on a lateral view of the sacrum. Likewise, radioisotope accumulation in the bladder can obscure a sacral tumor on a bone scan. More than 50% of chordomas exhibit radiographically detectable calcification. CT may be better for detecting calcification (which may help with the diagnosis), but MRI is better for determining the full extent of the lesion and its relationship to other anatomic structures. A common pitfall in the evaluation of a patient with a chordoma and low back pain is ordering an MRI of only the lumbar spine; this study usually misses a sacrococcygeal chordoma because most arise below S3.

Microscopically, chordoma appears as lobules of cells separated by fibrous bands. The cells usually contain abundant vacuolated cytoplasm (physaliferous cells). The cells usually are arranged in long strands, or “cords,” with a mucinous background. Most chordomas are low grade, although dedifferentiated chordomas exist. These dedifferentiated chordomas contain areas of a high-grade sarcoma (most frequently an MFH) and behave in a more aggressive manner.

The primary treatment is surgical resection with wide margins, even if this creates a neurologic deficit, because progressive growth of the tumor would create a neurologic deficit anyway and possibly metastatic disease. Resection that preserves the S3 nerve roots bilaterally results in relatively normal bowel and bladder function, whereas resection above this level results in incremental loss of bowel and bladder function. Resection of bilateral S2 nerve roots results in complete loss of control of bowel and bladder function. If wide margins cannot be obtained or if tumor contamination occurs intraoperatively, radiation may be beneficial. Radiation may also be beneficial for patients in whom resection is not feasible, although a cure is rarely, if ever, achieved in these patients. Chemotherapy is of no proven benefit. Likewise, distant metastases are treated surgically.

The 5-year overall survival rate for patients with chordomas is approximately 60% to 80%, but the survival rate continues to decline with longer follow-up because of late recurrences (25% to 60% 10-year survival). Local recurrences are common because of the difficulty encountered in achieving wide margins. Male gender and younger age at diagnosis have been reported to be associated with a favorable prognosis. A more distal location for sacral lesions is also associated with a better prognosis. Metastases are rare at initial presentation (<5%) but may occur later in 30% to 60%. In addition to the lungs, metastases are common in bone and have been reported and in unusual locations such as skin, eyelid, brain, liver, and other internal organs.

Adamantinoma

Adamantinoma is a rare neoplasm representing less than 1% of all primary malignancies of bone. Adamantinoma has a wide age distribution, but most patients are in the second or third decade at the time of diagnosis. It has a peculiar predilection for occurring in the tibia (approximately 85%) and may also involve the ipsilateral fibula. It has been postulated that adamantinoma arises from aberrant nests of epithelial cells, which would account for the fact that this tumor primarily occurs in bone that is in a subcutaneous location.

Pain is the most common symptom. The lesion is typically slow growing; therefore, the pain can be present for many years before the patient seeks medical attention. Because the lesion usually occurs in a subcutaneous location, a palpable mass may be present. Approximately 20% of patients have a pathologic fracture.

The most common radiographic appearance is that of multiple, sharply demarcated radiolucent lesions in the tibial diaphysis ( Fig. 27.15 ). The radiolucent lesions are separated by areas of dense, sclerotic bone. Although the radiographic appearance is similar to that of osteofibrous dysplasia, adamantinoma usually has a more aggressive appearance. A large portion or even the entire tibia can be involved. Frequently, the fibula is also involved by direct extension of the tumor.

Microscopically, adamantinoma consists of islands of epithelial cells in a fibrous stroma. Some areas of the tumor can resemble fibrous dysplasia or osteofibrous dysplasia. (Some authors consider adamantinoma to be a malignant variant of osteofibrous dysplasia.) Nuclear atypia is minimal, and mitotic figures are rare. Immunohistochemical staining usually is positive for cytokeratins and vimentin. It generally is a low-grade lesion, and histologic features are not predictive of behavior.

The optimal treatment of adamantinoma is wide resection or amputation. The tumor generally is radioresistant and chemoresistant. Local recurrence occurs in approximately 25% of patients, and amputation should be considered for these patients. Metastases are rare at presentation but may occur later in 30% of patients. Overall survival is approximately 85% at 10 years. Prognosis depends most on the adequacy of the surgical margin. Compared with patients who have marginal or intralesional surgical procedures, patients who have wide or radical procedures have significantly reduced rates of local recurrence and metastases (<10%). Because of the slow-growing nature of this lesion, local recurrence or metastasis may occur very late, reportedly 19 years after the initial treatment. The importance of long-term follow-up must be stressed.

Malignant Vascular Tumors

The terminology used to describe malignant vascular tumors in the literature is confusing. Multiple terms have been used interchangeably, including hemangioendothelioma, hemangioendothelial sarcoma, hemangiosarcoma, angiosarcoma, and others. Although not strictly defined, most authors use the term hemangioendothelioma to describe low-grade malignant vascular tumors and the term angiosarcoma to describe high-grade malignant vascular tumors.

These are rare tumors. After the first decade, they may occur at any age and in any bone. There is a slight male predominance but no significant race predilection. Stewart-Treves syndrome refers to the occurrence of angiosarcoma in the setting of chronic lymphedema (e.g., in the upper extremity of a patient who has previously undergone a radical mastectomy). Angiosarcomas have also been reported to occur adjacent to orthopaedic implants, although a causal relationship has not been firmly established.

Pain or, more rarely, pathologic fracture is the presenting complaint. Duration of symptoms varies depending on the grade of the tumor. The radiographic appearance of this lesion is also correlated with its grade. Low-grade tumors appear as well-demarcated lytic lesions that may or may not have surrounding reactive bone formation ( Fig. 27.16 ). High-grade tumors have a more permeative appearance. Periosteal reaction is unusual. Malignant vascular tumors have a peculiar tendency to be multicentric at presentation regardless of grade. Most commonly, multiple lesions are found within the same bone or within multiple bones of the same extremity.

Microscopically, low-grade tumors show well-formed anastomosing vascular channels lined by plump endothelial cells. Well-differentiated hemangioendotheliomas can be difficult to differentiate from benign hemangiomas. High-grade lesions can be pleomorphic and may appear as an undifferentiated sarcoma or carcinoma. In some extremely pleomorphic lesions, the diagnosis can be made only through immunohistochemistry. Although metastatic carcinoma and malignant vascular tumors may be keratin positive, factor VIII–related antigen, CD31, and CD34 should be positive only in vascular tumors.

Treatment is individualized depending on the clinical situation. Solitary lesions are treated with wide resection if possible. Radiation can be used successfully in the treatment of surgically inaccessible lesions or in the treatment of multiple lesions. For high-grade lesions, adjuvant chemotherapy can be added to the treatment regimen. Prognosis depends most on grade. Patients with low-grade lesions may have better than an 80% chance for long-term survival, whereas patients with high-grade tumors have less than a 20% long-term survival rate.

Malignant Fibrous Histiocytoma and Fibrosarcoma

Although MFH and fibrosarcoma are described in the literature as being separate entities, the distinction is sometimes arbitrary. The presentation, prognosis, and treatment of these two entities are similar, and so they are discussed together.

Excluding the first decade, they occur at any age with comparable frequency. Both men and women are affected equally. There is a slight tendency for the lesion to occur in the distal metaphysis of the femur or the proximal metaphysis of the tibia; however, any bone may be involved. Approximately 25% of these tumors are considered to be secondary to a preexisting bone abnormality. The most commonly reported predisposing conditions include Paget disease, radiation, giant cell tumor, and bone infarction ( Fig. 27.17 ). They may also occur as part of a dedifferentiated chondrosarcoma.

As is the case with other bone sarcomas, patients complain of pain at presentation. These patients have a higher incidence (approximately 20%) of pathologic fracture at presentation. Radiographically, these tumors have an aggressive appearance and are typically purely lytic with indistinct borders. They may appear as an area of bone destruction adjacent to an otherwise typical area of Paget disease or bone infarction. Periosteal reaction is absent, unless a pathologic fracture has occurred.

Histologically, the classic appearance of MFH is a high-grade spindle cell sarcoma arranged in a storiform or cartwheel pattern. The appearance can vary, however. Tumors may exhibit benign and malignant multinucleated cells, cells with a histiocytic appearance (large, indented nuclei with abundant, well-defined cytoplasm), cells with foamy cytoplasm, inflammatory cells, and variable amounts of fibrosis. The classic appearance of fibrosarcoma is that of a spindle cell neoplasm arranged in a herringbone pattern. Low-grade fibrosarcomas may exhibit abundant collagen production, whereas high-grade tumors are more cellular. MFH and fibrosarcoma are characterized by the lack of osteoid production. Even a small amount of osteoid production by the malignant cells would change the diagnosis to osteosarcoma.

At most institutions, the treatment of MFH of bone and fibrosarcoma of bone is similar to that of osteosarcoma. Most patients with high-grade lesions are treated with neoadjuvant chemotherapy, followed by surgery (wide resection or wide amputation) and adjuvant chemotherapy. Compared with osteosarcoma, however, MFH may be more radiosensitive. There are reports of long-term survivors of MFH of the spine who were treated with radiation alone. Radiation therapy may also be beneficial for patients with positive resection margins or intraoperative tumor contamination.

The prognosis is based on the presence or absence of metastases, the size and location of the tumor (as they relate to the ability of the surgeon to remove the tumor with wide margins), the grade of the tumor, and the histologic response to preoperative chemotherapy (as determined by percent necrosis). Reports have also shown older age to be associated with a worse prognosis; however, this may be caused partially by the inability of many older patients to tolerate chemotherapy. No difference in prognosis has been shown between patients with primary tumors and patients with tumors arising in a predisposing condition. Overall, the 5-year survival rate for patients with high-grade tumors of the extremities without metastases at presentation is approximately 65%.

Multiple Myeloma and Plasmacytoma

Multiple myeloma is the most common primary malignancy of bone. Its peak incidence is in the fifth to seventh decades with a 2:1 male predominance. Multiple myeloma and metastatic carcinoma should be included in the differential diagnosis for any patient older than 40 years with a new bone tumor.

Bone pain is the most common complaint for patients with multiple myeloma or with a solitary plasmacytoma. In contrast to most bone tumors, however, other systemic problems, such as weakness, weight loss, anemia, thrombocytopenia, peripheral neuropathy (especially with the osteosclerotic type of multiple myeloma), hypercalcemia, or renal failure, frequently are present at the time of diagnosis of multiple myeloma. Symptoms usually are of short duration because of the aggressive nature of the disease. Pathologic fractures are relatively common. The spine is the most common location, followed by the ribs and pelvis.

Radiographically, multiple myeloma appears as multiple, “punched-out,” sharply demarcated, purely lytic lesions without any surrounding reactive sclerosis ( Fig. 27.18 ). The lack of reactive bone formation is also shown by the fact that most lesions are negative on bone scan. (A less common variant of multiple myeloma is characterized by extensive sclerosis.) Occasionally, myeloma is characterized by marked bone expansion, giving rise to a “ballooned” appearance.

The diagnosis usually can be confirmed by serum immunoelectrophoresis, which shows a monoclonal gammopathy. In addition to a complete blood cell count and serum chemistries, staging studies include a skeletal survey and a bone marrow biopsy. Occasionally, biopsy of the bone lesion is required to establish the diagnosis.

Histologically, multiple myeloma appears as sheets of plasma cells. These are small, round blue cells with “clock face” nuclei and abundant cytoplasm with a perinuclear clearing or “halo.” Amyloid production can be abundant. With the exception of patients on long-term hemodialysis, the presence of amyloid in bone usually means a diagnosis of multiple myeloma. In patients with a solitary plasmacytoma, the pathologic differential diagnosis may include chronic osteomyelitis with abundant plasma cells ( Fig. 27.19 ). In this situation, immunohistochemistry can be helpful. Plasmacytoma exhibits monoclonal κ or λ light chains, whereas the plasma cells of chronic osteomyelitis are polyclonal. Also, myeloma cells usually stain positive for the natural killer antigen CD56, whereas reactive plasma cells usually do not. Immunohistochemistry can also be helpful in poorly differentiated cases when lymphoma could be in the differential diagnosis. Lymphoma cells usually stain positive for CD45 (leukocyte common antigen) and CD20 (a B-cell marker), whereas myeloma cells usually are negative.

The primary treatment of multiple myeloma is chemotherapy. Symptomatic bone lesions usually respond rapidly to radiation therapy. Bisphosphonates have also been shown to be of benefit in the prevention of skeletally related events. The orthopaedic surgeon most commonly is consulted to treat impending or actual pathologic fractures of the spine, acetabulum, proximal femur, or proximal humerus. Every effort should be made to perform the operation that would allow the earliest resumption of full activity. This may include debulking the tumor and using internal fixation augmented with methacrylate. If this method would not allow immediate full weight bearing, cemented total joint arthroplasty or hemiarthroplasty should be considered. In most patients, local radiation therapy should be instituted 2 to 3 weeks after surgery or when the wound appears to be healed. The treating surgeon should keep in mind, however, that patients with myeloma are at higher risk for perioperative complications (e.g., infection, deep vein thrombosis, or renal failure) when compared with most orthopaedic patients.

Patients who present with a solitary plasmacytoma without evidence of systemic involvement (i.e., negative bone marrow biopsy and negative skeletal survey) have a better prognosis. Although more than half of patients who present with a solitary plasmacytoma eventually go on to develop multiple myeloma, some patients have a considerable disease-free interval, and a few remain continuously free of disease. Until recently, long-term survival for patients with multiple myeloma was very rare. Currently, however, some centers are reporting greater than 60% long-term survival with aggressive treatment.

Lymphoma

Lymphoma may involve bone primarily or secondarily. Lymphoma can occur at any age but becomes more common in the sixth and seventh decades of life. The male-to-female ratio is approximately 1.5:1. The femur is the most common bone involved, followed by the pelvis, spine, and ribs.

Most patients complain of localized pain or swelling. Patients with spinal involvement may have nerve root or cord compression. The symptoms can be mild or severe. Some patients have symptoms for several years before seeking medical attention. In contrast to patients with multiple myeloma, patients with lymphoma usually feel otherwise healthy.

Radiographically, lymphoma usually appears as an ill-defined area of bone destruction (frequently diaphyseal) and often has a permeative appearance. The cortex may be thickened, but a periosteal reaction rarely is seen. Frequently, a large portion of the bone or even the entire bone can be involved. The extent of the lesion may appear large compared with the patient’s symptoms. Radiographs can be entirely normal despite extensive involvement of the medullary canal as seen on bone scan or MRI ( Fig. 27.20 ). (Lymphoma usually should be included in the differential diagnosis of a patient who has bone pain and an abnormal bone scan or MRI with normal radiographs.) The soft-tissue mass can also be extensive. Staging studies should include a complete blood cell count and serum chemistries; bone scan; CT of the chest, abdomen, and pelvis; and a bone marrow biopsy. Whole body PET/CT is also useful for staging as well as for evaluation of response to treatment.

Microscopically, osseous lymphomas are composed of a mixture of large and small lymphoid cells with cleaved and noncleaved nuclei ( Fig. 27.21 ). Some may appear sarcomatoid, and others may be difficult to distinguish from Ewing sarcoma or an undifferentiated carcinoma. Immunohistochemistry (specifically, positive staining for lymphoid markers, positive reticulin stain, negative keratin, and negative PAS) frequently is helpful in these cases.

A discussion of the classification of lymphomas is beyond the scope of this text. In general, however, patients with primary lymphoma of bone have a better prognosis (approximately 50% to 80% 5-year survival) than patients with systemic disease. The primary treatment of lymphoma is chemotherapy ( Fig. 27.22 ) . Local control usually is attained with radiation therapy. Surgical intervention is rarely needed but may be indicated for treatment of impending or actual pathologic fractures.

Metastatic Carcinoma

Metastatic carcinoma is the most common malignancy treated by orthopaedic surgeons. Although only about 8000 new sarcomas are diagnosed in the United States each year, more than 1 million new carcinomas are diagnosed. It is estimated that 50% to 80% of patients with carcinoma have bone metastases at the time of death. As treatment for primary tumors improves, longer survival time is being reported after diagnosis of bone metastases. The orthopaedic surgeon should not approach these patients with a fatalistic attitude. Proper orthopaedic care is crucial for many of these patients to minimize pain, maintain function, maintain their independence, and improve their overall quality of life.

If a patient has a known history of a carcinoma, even in the remote past, a newly discovered bone lesion is most likely to be a metastasis. In any patient older than 40 years, even without a history of malignancy, a newly discovered, aggressive-appearing bone lesion is most likely to be metastatic carcinoma or multiple myeloma. The proper workup of a patient with suspected metastases of unknown origin is discussed in detail in Chapter 24 .

Briefly, the workup consists of a history and physical examination, including breast or prostate; basic laboratory tests, including serum protein electrophoresis and possibly prostate-specific antigen; a radiograph of the entire involved bone; a chest radiograph; a bone scan to look for other sites of disease; and CT of the chest, abdomen, and pelvis. Failure to complete this workup before biopsy can lead to serious errors in patient care. This simple approach identifies the primary lesion in more than 85% of patients who have metastases of unknown origin. After the workup is complete, a biopsy can be performed. Even if a patient has a known history of carcinoma, a biopsy of the first site of bone disease must be performed to establish a firm relationship between the primary carcinoma and the suspected metastasis. This biopsy must be done in the same manner as a biopsy for a suspected primary sarcoma because, in rare instances, it may prove to be a primary sarcoma ( Fig. 27.23 ). Subsequent bone metastases can be treated without biopsy confirmation.

Most carcinomas metastatic to bone are from the breast and prostate, followed by the lung, kidney, thyroid, and gastrointestinal tract in order of decreasing frequency. For patients who have suspected metastases of unknown origin, however, the most common primary malignancies are in the lung or kidney. Breast and prostate are uncommon sites of primary disease for this group of patients. This phenomenon has several possible explanations. First, the primary lesions in patients with breast cancer or prostate cancer may be detected more easily early in the disease course. Second, breast cancer and prostate cancer may not metastasize to bone until relatively late. Finally, lung and kidney cancer may escape detection until very late in the disease course and may metastasize to bone relatively earlier.

The radiographic appearance of metastatic carcinoma varies. The appearance usually is aggressive, suggesting malignancy. The lesions may be lytic, blastic, or mixed. Breast cancer and prostate cancer typically produce blastic lesions. Kidney cancer and thyroid cancer usually are purely lytic. Lung cancer may produce a mixed appearance. If the lesion is distal to the elbow or knee, lung cancer is the most likely primary lesion. In addition, metastatic lung cancer may have the distinct appearance of a “bite” taken out of the cortex.

The microscopic appearance of metastatic carcinoma usually is similar to that of the primary lesion. In well-differentiated cases, the biopsy easily yields the correct diagnosis. In some cases, such as a sarcomatoid kidney cancer, immunohistochemistry may be required to reveal epithelial markers.

The treatment of carcinoma metastatic to bone is multimodal. Systemic treatment with cytotoxic agents is directed by the medical oncologist. Hormone manipulation may be beneficial for patients with breast or prostate cancer. Radioactive iodine may be beneficial for some patients with metastatic thyroid cancer. Bisphosphonates have a role in preventing new metastatic bone lesions from forming and slow the growth of existing lesions by inhibiting osteoclast resorption of bone. Most symptomatic bone metastases are responsive to radiation. Some carcinomas, especially kidney cancer, are typically radioresistant. Some of these lesions can be treated with radiofrequency ablation or cryoablation. Surgery is required for treatment of impending or actual pathologic fractures.

Precisely defined indications for prophylactic fixation of impending pathologic fractures have been debated. Parameters that have been suggested include pain that has not responded to radiation therapy, a lesion larger than 2.5 cm, a lesion that has destroyed more than 50% of the cortex, and an avulsion fracture of the lesser trochanter. Mirels devised a scoring system that evaluates the risk of pathologic fracture on the basis of the site, size, and lytic or blastic nature of the lesion, as well as the presence and quality of associated pain ( Table 27.1 ). According to this system, prophylactic internal fixation should be considered for any patient with a score of 8 or higher. Although each of these guidelines aids in the decision-making process, none serves as an absolute criterion. Each patient should be evaluated individually while keeping two generally accepted principles in mind. First, prophylactic internal fixation of an impending fracture is technically easier than fixation of an actual pathologic fracture. Second, patient morbidity is decreased with prophylactic fixation compared with fixation after the fracture.

The prognosis of patients with metastatic carcinoma continues to improve. Although most patients with a pathologic fracture from metastatic lung cancer die within 6 months, length of survival is not always predictable. We have treated multiple patients who have survived with good quality of life 4 to 5 years after sustaining pathologic fractures secondary to metastatic lung cancer. Patients with breast, prostate, and kidney cancer commonly live many years after diagnosis of bone metastases. An isolated bone metastasis from kidney cancer can be treated with curative intent with wide resection ( Fig. 27.24 ).

The unpredictability of survival makes proper surgical care more challenging. The fixation must be stable enough to allow immediate full weight bearing so that a patient would not have to endure an unnecessarily prolonged rehabilitation period when he or she may have only several months to live. Conversely, the reconstruction should be durable enough to last for many years if the patient happens to do well. In general, the tumor should be debulked before internal fixation. The cavity can be filled with methacrylate to augment the fixation. The entire bone should be protected with intramedullary fixation in most cases ( Figs. 27.25 to 27.31 ). If this approach would not provide the stability required for immediate full weight bearing, resection and prosthetic reconstruction should be considered. Lesions of the femoral neck should be considered for hemiarthroplasty or total hip arthroplasty. Arthroplasty components frequently are fixed with cement because the bone usually is treated with radiation. Recent studies, however, have shown that modern press-fit implants, especially those made with trabecular metal appear to obtain adequate fixation in this setting. Radiation therapy usually is administered to the entire operative field beginning 2 to 3 weeks after surgery if the wound has healed. Due to the general medical condition of these patients, as well as the extent of the procedures combined with chemotherapy and radiation treatment, infection risk is relatively high. Surgeons should consider a prolonged course of postoperative antibiotics, although specific protocols need further study to prove efficacy.

A summary of the characteristics of malignant tumors of bone is presented in Table 27.2 .