Primary Bone Tumors

Conventional (High-Grade Intramedullary) Osteosarcoma

Conventional osteosarcoma is the most common primary bone sarcoma in the adolescent age group, accounting for approximately 85% of all cases of osteosarcoma. Seventy-five percent of cases occur in patients younger than 25 years. It most often arises in the long bones of the appendicular skeleton, particularly the distal femur, proximal tibia, and proximal humerus. Ninety percent are metaphyseal or metadiaphyseal, with only 10% diaphyseal. They are clearly highly aggressive tumors with permeative bone destruction, irregular cortical destruction, and complex periosteal reactions. The degree of malignant osteoid production can vary with a spectrum of radiographic appearances, from purely lytic to densely osteoblastic, although most show a mixed pattern ( Fig. 92-5 ). Textbooks understandably choose examples of osteosarcoma that tend to illustrate many or all of the typical features in a single case (see eFig. 92-1 ). In clinical practice, however, cases may only show one or two of the classic signs. The radiologist needs to be alert to the diagnostic possibility of a sarcoma and recognize the significance of a single sign, such as a Codman angle or subtle permeative bone destruction. Indeed, if the matrix mineralization is minimal, the osteosarcoma may be radiographically indistinguishable from other sarcomas, such as malignant round cell tumors. Whether a high-grade intramedullary osteosarcoma is principally lytic or sclerotic has little influence on either management or prognosis. Pathologic subdivision into osteoblastic (50%), chondroblastic (25%), and fibroblastic (25%) types is important because of differences in neo-adjuvant treatment schemes.

The diagnosis of an osteosarcoma is usually made after analysis of the radiographs with MRI largely used for staging purposes (see Chapter 99 ). Tumor infiltration of bone, irrespective of the precise histology, will show a T1-weighted signal that is isointense with surrounding muscle and is inhomogeneous but hyperintense on T2-weighted and short tau inversion recovery (STIR) images (see eFig. 92-2A ). Low–signal-intensity areas in osteosarcoma correlate well with matrix mineralization. The identification of cortical destruction and soft tissue extension with a solid soft tissue mass is a cardinal sign of a malignancy. Evidence of tumor on MRI beyond the confines of the host cortex is frequently taken to indicate soft tissue extension. In many cases, the tumor is displacing the periosteum rather than penetrating it and so remains intraosseous, albeit with considerably greater dimensions than the parent bone. When ignored, this may cause a discrepancy between the MRI findings and the pathologist's assessment of the extent of the excised tumor. Peritumoral edema, both medullary and soft tissue, may be seen with osteosarcoma and typically reduces after adjuvant chemotherapy. The degree of edema is significantly less florid than that seen in benign conditions, such as osteoid osteoma and chondroblastoma.

The use of dynamic contrast-enhanced MRI may be useful in revealing viable areas of tumor before biopsy and as a baseline measurement for subsequent assessment of tumor response to chemotherapy. Recently, diffusion-weighted imaging has shown promising results in the prediction of chemotherapy response in osteosarcoma ( eFig. 92-3 ). These initial findings, however, are based on a few studies with a small sample size and, therefore, require further validation in a larger patient cohort.

The significance of identifying growth plate, joint, and neurovascular involvement in osteosarcoma and other primary sarcomas of bone is discussed in Chapter 99 .

Bone scintigraphy will typically show marked increased activity over an osteosarcoma but again is largely reserved for staging purposes, that is, for confirming or excluding multifocal osteosarcomas or bone metastases ( eFigs. 92-2B and 92-5B ).

In less than 5% of cases, noncontiguous intramedullary growth within the parent bone or across adjacent joints may occur. It is important that these so-called skip metastases are confirmed or excluded on the initial staging studies because this will influence subsequent surgical options ( Fig. 92-6B ). Whole-body bone scintigraphy or, more recently, whole-body MRI are being used to evaluate the presence of skeletal metastases.

Whole-body MRI is a promising tool in the assessment of skeletal metastases because it has been shown to have a higher sensitivity and at least a similar specificity when compared with skeletal scintigraphy. Furthermore, whole-body MRI allows assessment of bone marrow infiltration without the need for ionizing radiation ( eFig. 92-4 ).

High-grade intramedullary osteosarcoma has a high metastatic potential, particularly through hematogenous spread to the lungs. Five to 10% of cases will have pulmonary metastases at initial presentation. After initial treatment with limb-salvage surgery (if practicable) and chemotherapy, disease relapse may arise due to local recurrence or the development of distant metastases, which typically are pulmonary. Because of the high-grade nature of these tumors, this usually occurs within 2 to 3 years. The use of chemotherapy has greatly improved the prognosis for patients with a high-grade intramedullary osteosarcoma over surgery alone. The 5-year survival rate for most series of patients without evidence of metastatic disease at presentation is approximately 65%. Chemotherapy has modified the natural history of the disease, not just in terms of long-term survival but also in site of metastases. Approximately 15% of patients who subsequently develop metastases do so in the bones in the absence of imaging evidence of pulmonary disease.

Pathologists recognize a small cell variant of osteosarcoma that histologically resembles Ewing sarcoma. It is of only passing interest to radiologists because the clinical and imaging features are indistinguishable from those of high-grade intramedullary osteosarcoma.

Multicentric Osteosarcoma

Approximately 1.5% of cases of osteosarcoma are classified as multicentric (multifocal). These tumors can be synchronous or metachronous in presentation, that is, multiple tumors identified at initial presentation or delayed over time ( eFig. 92-5 ). For the diagnosis to be made, multiple bones are involved in the absence of pulmonary metastases. Whole-body bone scintigraphy or whole-body MRI will show the full extent of bone involvement with usually the index lesion being somewhat larger than the other lesions (see eFigs. 92-2AB and 92-5 ). This does beg the question as to whether multicentric osteosarcoma is a separate entity or a different manifestation of metastatic disease. It is likely that this is a diagnosis made less frequently than in the past because multislice CT is more sensitive in the detection of small lung nodules.

Telangiectatic Osteosarcoma

Telangiectatic osteosarcoma accounts for approximately 4% of all cases of osteosarcomas and has a minor male preponderance. It is a high-grade tumor that is most common in the second decade and affects the femur and tibia. It is predominantly lytic with aggressive features on radiographs ( Fig. 92-6 ). Histologically, it comprises multiple hemorrhagic spaces separated by thin septa. For this reason, it may mimic both radiologically and histologically an aneurysmal bone cyst with fluid-fluid levels frequently identified on MRI. Clearly, it is of paramount importance to distinguish the two entities because the management and prognosis differ significantly.

Low-Grade Central Osteosarcoma

Low-grade central osteosarcoma accounts for less than 1% of all osteosarcomas. Typical sites include the femur and tibia ( eFig. 92-6 ). It is, as the name indicates, entirely intramedullary in location with nonaggressive radiographic features that frequently mimic either fibrous dysplasia or a cartilage lesion. For this reason, diagnosis is often delayed. Because of its rarity, the authors are reluctant to advise including it in the routine differential diagnosis of benign bone lesions. However, it is worth keeping the diagnosis in mind if biopsy of an otherwise innocuous bone lesion appears to show subtle malignant osteoid.

Immunohistochemistry can aid in the histologic diagnosis of low-grade central osteosarcoma. Expression of murine double-minute type 2 and cyclin-dependent kinase 4 has been found in all low-grade osteosarcomas but not in benign fibro-osseous lesions. It is nevertheless vital to consider the diagnosis of a low-grade central osteosarcoma when faced with the dilemma of an unusual fibro-osseous lesion because these immunohistochemical tests may not be routinely performed in the histologic assessment of fibro-osseous lesions.

Surface Osteosarcoma

There are three types of surface or juxtacortical osteosarcoma that make up less than 7% of all osteosarcomas. These are the parosteal, periosteal, and high-grade surface variants.

Parosteal Osteosarcoma

Parosteal osteosarcoma is the second most common type of osteosarcoma and accounts for approximately 5% of cases. It is seen in a slightly older age group than high-grade intramedullary osteosarcoma, typically presenting in the third and fourth decades. Because it is a low-grade malignancy, the prognosis is better, with a greater than 95% 5-year survival after surgical excision, with chemotherapy used in cases associated with dedifferentiation only. Greater than 50% of cases arise on the posterior aspect of the distal femoral metaphysis (see Fig. 92-7 ). Other sites include the proximal tibia and proximal humerus. The tumor is slow growing and is usually relatively large at presentation with particularly dense sclerosis due to mature osteoid, as compared with the immature osteoid typical of most high-grade osteosarcomas. The tumor is lobulated and wraps around the outer cortex of the underlying bone. Although it may be in contact with the cortex, some areas will show a plane of cleavage readily visible on CT. On MRI, up to 50% of cases will show evidence of cortical destruction with medullary invasion (see Fig. 92-7B ). Up to 20% of cases either at presentation or on recurrence will show dedifferentiation to a high-grade osteosarcoma. This should be suspected if there is a significant soft tissue component to the tumor. Biopsy should be directed to any suspected high-grade areas of the tumor because this will influence management. The differential diagnosis for parosteal osteosarcoma includes other mineralizing surface lesions, such as surface osteoma and myositis ossificans as well as osteochondroma. The surface form of myositis ossificans (periostitis ossificans) can be diagnosed by identification of the zoning phenomenon, whereby calcification and subsequent ossification first develops in the periphery of the lesion (see eFig. 92-7 ). This is in contrast to parosteal osteosarcoma, in which the matrix is densest centrally and may be less mature or absent peripherally. Parosteal osteosarcoma differs from osteochondroma in that the latter shows flaring of the cortex continuous with the cortex of the underlying bone and a trabecular component merging with the medulla of the host bone. Because it is a low-grade tumor, local recurrence may occur many years after presentation and initial surgical management.

Periosteal Osteosarcoma

Periosteal osteosarcoma accounts for less than 2% of cases of osteosarcoma. It tends to occur in adolescents and young adults and arises most often from the surface of the diaphyses of the tibia and femur ( Fig. 92-8 ). It is a low- to intermediate-grade tumor with prominent chondrogenic components. There is a spectrum of imaging appearances ranging from features suggestive of a periosteal chondroma (due to the chondrogenic elements) with scalloping of the outer cortex to a patently more aggressive lesion with Codman angles and a spiculated/sunburst periosteal reaction (see Fig. 92-8 ). The latter appearances resemble a high-grade surface osteosarcoma (see later discussion). MRI confirms the surface nature of the tumor with intramedullary invasion uncommon.

High-Grade Surface Osteosarcoma

High-grade surface osteosarcoma, as the name implies, is a high-grade malignancy indistinguishable histologically from the intramedullary counterpart—the only difference being the surface origin. It is the rarest of the surface osteosarcomas, accounting for less than 1% of all osteosarcomas. The most frequent sites are the femur, tibia, and humerus ( Fig. 92-9 ). Radiographically, these tumors resemble the more aggressive end of the spectrum of periosteal osteosarcoma, with prominent spiculated periosteal new bone formation and intramedullary invasion more common.

Secondary Osteosarcoma

Secondary osteosarcoma develops in a preexisting bone lesion that may or may not be neoplastic (see Table 92-2 ). One distinctive feature of these secondary lesions is that they tend to occur in an older age group than primary osteosarcoma (e.g., Paget osteosarcoma). This can have major implications on management because many affected patients are too old to undergo chemotherapy. This adversely affects the prognosis and ultimately the long-term survival of these patients.

Dedifferentiated chondrosarcoma is discussed later under cartilage-producing tumors.

Paget disease of bone, named after the nineteenth century British surgeon, Sir James Paget, is a localized or multifocal disorder of bone characterized by abnormal bone turnover with increased osteoclastic activity and compensatory increased osteoblastic activity. The prevalence of Paget disease increases with age, with significant geographic/ethnic variations. It is relatively common in the white races of Northern Europe and yet rare in blacks and Asians. Recent studies, however, have shown that the disease is slowly disappearing. Of all of the skeletal complications seen in Paget disease, malignant transformation is by far the most serious and typically presents in the sixth and seventh decades of life. Paget sarcoma is twice as common in men than in women, is more common in patients with multifocal disease, and typically presents in the sixth and seventh decades of life. The most commonly affected bones, in descending order of frequency, are the femur, pelvis, and humerus ( eFig. 92-8 ). By far, the most frequent histology of Paget sarcoma is osteosarcoma. In those regions where Paget disease is common, 20% of patients with osteosarcoma who are older than 40 years and as high as 50% of patients with osteosarcoma older than 60 years have Paget disease as the predisposing condition. In the older literature, the second most common histology in Paget sarcoma was fibrosarcoma. More recent pathologic redefinition of spindle cell sarcomas means that other diagnoses, such as undifferentiated high-grade pleomorphic sarcoma and leiomyosarcoma, tend to be favored over fibrosarcoma. The majority of Paget sarcomas will show rapidly progressive ill-defined bone destruction developing within an area of preexisting Paget disease. Cortical destruction and a soft tissue mass are common features, whereas periosteal new bone formation is seen in less than 20% of cases. Despite that most are secondary osteosarcomas, radiographically apparent malignant osteoid is not common. Unlike most sarcomas of bone, Paget sarcoma frequently appears relatively photopenic against the background of increased activity of Paget disease on bone scintigraphy. In uncomplicated Paget disease, the fat signal (hyperintense on both T1- and T2-weighted images) is typically preserved in all phases of the disease. Paget sarcoma, unless densely mineralized, typically shows intermediate- to low–signal-intensity tumor tissue on T1-weighted images with corresponding high signal intensity on T2-weighted or short tau inversion recovery (STIR) images. Most cases will show cortical destruction with a soft tissue mass. It is important to recognize that not all tumors arising in Paget disease are sarcomas. There is a recognized association between Paget disease and giant cell tumors of bone. Also, in the elderly population, metastases, myeloma, and lymphoma may all develop in pagetic bone. Tumor-like conditions that may mimic Paget sarcoma include pseudosarcoma due to the development of florid periosteal pagetic bone, accelerated disuse osteoporosis usually after immobilization, and drug-induced osteomalacia.

Radiation-induced sarcomas of bone are rare, accounting for approximately 1.5% of all bone sarcomas. The overall incidence ranges between 0.03% (of patients who receive radiation) and 0.2% (of patients who received radiation and survived 5 years). Sarcomas can develop in any bone exposed to either internal or external radiation sources. They may arise at the site of preexisting bone lesions or in bones that were normal at the time of irradiation, such as when radiation has been used to treat malignancy in adjacent soft tissue tumors without bony involvement. Approximately one third of postirradiation sarcomas arise in preexisting lesions such as giant cell tumor, bone lymphoma, osteosarcoma, or round cell tumors, such as Ewing sarcoma. There was a vogue in the mid-twentieth century, long since ceased, to treat fibrous dysplasia with radiotherapy. As a result, radiation sarcomas were seen in association with fibrous dysplasia. Osteosarcoma and spindle cell sarcoma (fibrosarcoma, undifferentiated high-grade pleomorphic sarcoma) account for greater than 90% of radiation-induced sarcomas. Chondrosarcomas comprise less than 10% of the total. Established diagnostic criteria for the diagnosis of postirradiation sarcoma are (1) malignancy arising within the irradiated field; (2) histologic proof of sarcoma, distinct from any original lesion; and a (3) long latent period of at least 4 years after irradiation. The latent period ranges from 4 to 55 years (mean, 11 to 14 years). It does not differ between children and adults, but, in children, a higher prevalence of radiation-induced sarcoma can be expected because the immature skeleton is more susceptible to radiation-induced induction of malignancy and because they have a longer period over which they are at risk and therefore have the potential to develop malignancy. Latency may be inversely proportional to radiation dose, with shorter latent periods often seen after administration of higher doses. Radiographically, an aggressive lytic lesion is present often with soft tissue extension ( eFig. 92-9 ). Malignant osteoid formation with dense sclerosis is a feature of radiation-induced osteosarcoma. Coexisting radiation bone changes are seen in up to 50% of patients. The cardinal features of cortical destruction and soft tissue extension are optimally demonstrated with MRI, but CT can also be used. Radiation-induced insufficiency fractures may mimic sarcoma or metastases, particularly on bone scintigraphy. These tend to occur at classic sites, for example, the sacrum in women who have undergone pelvic radiotherapy for a gynecologic malignancy. Chemical shift imaging (in-phase/opposed-phase MRI) can be a useful adjunct in the differentiation of malignant infiltration from radiation-induced insufficiency fractures or osteonecrosis ( eFig. 92-10 ). Chemical shift imaging is based on the observation that marrow infiltrative processes, such as malignant neoplasms, usually replace bone marrow, whereas nonmalignant processes tend to preserve bone marrow. If both fat and fluid are located within the same voxel, this results in a loss of signal on the opposed-phase images when compared with the in-phase images. Chemical shift imaging, therefore, allows the detection of fat within a skeletal lesion and, therefore, may be able to differentiate marrow-replacing processes, for example, malignant lesions from marrow-sparing processes, such as bone marrow edema, which is frequently seen in patients with insufficiency fractures or osteonecrosis. At this institution, chemical shift imaging has been routinely adopted in the assessment of patients with bone neoplasms in view of the added value and the fast acquisition times (approximately 1 minute).

Other conditions that rarely may be associated with the development of a secondary osteosarcoma as well as spindle cell sarcoma (undifferentiated high-grade pleomorphic sarcoma) are fibrous dysplasia, medullary infarction (see eFig. 92-11 ), and chronic osteomyelitis. Increasing pain, medullary lysis, cortical breaching, and the development of a soft tissue mass, often without obvious radiographic evidence of malignant osteoid formation, should suggest the possibility of malignant transformation and prompt further investigation with MRI.

Bone sarcomas have been rarely described arising adjacent to orthopedic implants, raising speculation as to an association. As yet, no convincing causal relationship has been proven in these cases.