The Many Faces of Osteosarcoma

Abstract Introduction Primary Intramedullary Osteosarcoma

Surface Osteosarcoma Extraskeletal Osteosarcoma Secondary Osteosarcoma

Conclusions Source Information References

Primary Intramedullary Osteosarcoma

The vast majority of osteosarcomas arise in the medullary canal. The intramedullary form of osteosarcoma is defined as tumor that originates within the medullary canal and often involves the entire width of the bone. These lesions have been categorized into numerous types, largely on the basis of histologic appearance.

High-Grade Intramedullary Osteosarcoma

The high-grade intramedullary variant of osteosarcoma accounts for approximately 75% of all lesions and is also referred to as central or conventional osteosarcoma (1,2,3,4). Most cases of high-grade intramedullary osteosarcoma are seen in patients in the 2nd and 3rd decades of life, with 75% of cases encountered in patients 15-25 years of age (1,2,3,4). Primary osteosarcoma occurring in patients younger than 6 years of age or older than 60 years of age is unusual. Osteosarcoma typically affects whites and males, with a male-to-female ratio of 1.5-2:1 (1,2,3,4,5). In fact, the incidence of osteosarcoma in black females is nearly five times less than that for white males (1,2,3,4,5). There have been isolated reports of a familial form of osteosarcoma, but the vast majority of cases occur as sporadic tumors (6). As with all types of osteosarcoma, the clinical manifestations are usually nonspecific, with pain and swelling being the most frequent symptoms. Patients commonly have a history of trauma, which brings the lesion to clinical attention. Pathologic fracture is seen in approximately 15%-20% of cases, either at presentation or during therapy (1,2,3,4).

High-grade intramedullary osteosarcoma most frequently affects long bones (70%-80% of cases), particularly about the knee (50%-55%) (1,2,3,4,5). Specifically, the femur is involved in 40%-45% of cases (Figure 1), the tibia in 16%-20% (Figure 2), and the humerus in 10%-15% (1,2,3,4,5). Involvement of the pelvis, fibula, facial bones, and spine is unusual, and the skull, clavicle, ribs, scapula, forearm, and small bones of the feet and hand are rarely affected. The majority (90%-95%) of high-grade intramedullary osteosarcomas arise in the metaphysis (1,2,3,4,5). Primary involvement of the diaphysis is seen in 2%-11% of cases, and these patients may have a longer duration of symptoms prior to diagnosis (Figure 3) (7,8). Although osteosarcoma with metaphyseal involvement often extends into the epiphysis (75%-88% of cases with open physis), initial manifestation within the epiphysis is very rare (<1%) (1,2,3,4,9,10).

Osteosarcoma is pathologically classified as a malignant mesenchymal neoplasm in which the tumor cells directly produce osteoid or immature bone (Figure 1d). Many lesions also contain other elements, particularly fibrous or chondroid components, but, by convention even if only a minority of the intraosseous tumor is producing osteoid, it is designated as an osteosarcoma. Macroscopically, osteosarcoma is usually a large (5-10-cm) intraosseous tumor with frequent soft-tissue extension (Figure 1, Figure 2, Figure 3). Mineralized regions of osteoid and cartilage as well as hemorrhagic foci are frequent. Histologically, osteosarcoma has classically been divided into osteoblastic, chondroblastic, and fibroblastic varieties, depending on the predominant cell type present. Although many lesions have a mixed histologic appearance, the predominant pattern is osteoblastic in 50%-80% of osteosarcomas (Figs 1-3), fibroblastic-fibrohistocytic in 7%-25%, and chondroblastic in 5%-25% (1,2,3,4). At histologic analysis, reactive new bone from many reparative processes including fracture can resemble osteosarcoma, and correlation of histologic findings with radiologic results is essential to ensure correct diagnosis. As with other malignant neoplasms, osteosarcoma is graded from I to IV according to the degree of anaplasia, although the prognostic significance of this parameter is controversial.

As in all cases of a bone lesion, the primary evaluation of an osteosarcoma begins with radiographic assessment. High-grade intramedullary osteosarcomas are aggressive lesions with rapid doubling times (20-30 days) and therefore are often large (typically >6 cm) at the time of diagnosis. At radiographic examination, the vast majority (approximately 90%) of osteosarcomas demonstrate a variable amount of fluffy, cloudlike opacities within the lesion, characteristic of osteoid matrix production (Figs 1-3) (1,2,3,4). Occasionally, the lesion may be completely blastic or lytic (fibroblastic type), but a mixed pattern of sclerosis and lucent areas is most frequent (Figure 2). High-grade intramedullary osteosarcoma tends to violate the cortex without expanding the osseous contours, a characteristic that reflects its aggressive pathologic behavior. This growth pattern is associated with aggressive periosteal reaction (Codman triangle, laminated, hair-on-end, or sunburst patterns) and soft-tissue masses in 80%-90% of cases (Figure1, Figure 2, Figure 3) (1,2,3,4).

Most osteosarcomas have a radiographic appearance that poses little diagnostic dilemma. Additional imaging techniques such as CT, MR imaging, and bone scintigraphy are typically not needed to diagnose an osteosarcoma. However, unusual radiographic appearances can lead to delay in diagnosis and confusion with benign diseases (11). This situation is particularly likely when the osteosarcoma involves anatomically complex areas such as the pelvis and in the case of small lesions (often <5 cm and adjacent to the endosteum). In these cases, cross-sectional imaging may not only help confirm the presence of the lesion but also help identify mineralized matrix that is not appreciable at radiography. More important, these imaging modalities are vital in the preoperative assessment and staging of osteosarcoma (12,13,14,15).

At bone scintigraphy, marked uptake of radiotracer is seen on blood flow, blood pool, and delayed images (Figure 2d). Presently, however, the chief role of scintigraphy is in evaluating for distant metastases. Both osseous and extraosseous metastatic disease may be detected.

The aggressive characteristics of high-grade intramedullary osteosarcoma, both intraosseous and soft-tissue components, are also well seen at CT (11,15,16,17). Nonmineralized portions of tumor are usually of soft-tissue attenuation and replace the normal low attenuation of fatty marrow (Figure 2c). Chondroblastic components may be of low attenuation on CT scans, reflecting a higher water content. Areas of central hemorrhage or necrosis, which also have low attenuation, are frequent. Osteoid matrix production is easily appreciated in both intraosseous and soft-tissue tumor components as areas of very high attenuation (Figure 2c). The chief advantage of CT is its ability to demonstrate small areas of mineralized matrix that might not be detected with MR imaging in predominantly lytic lesions.

MR imaging has become the cross-sectional imaging modality of choice for preoperative evaluation and staging of osteosarcoma because of its superior contrast resolution and multiplanar capabilities (9,10,12,13,14). Tumor is seen primarily as areas of intermediate signal intensity on T1-weighted images and as areas of high signal intensity replacing the normal marrow on T2-weighted images (Figure 1, Figure 2). Areas of low signal intensity on both T1- and T2-weighted MR images are frequent and represent mineralized matrix (Figure 1, Figure 2). Foci of central hemorrhage (which have high signal intensity with all MR pulse sequences) and necrosis (which has low signal intensity on T1-weighted images and high signal intensity on T2-weighted MR images) are common in both the intraosseous and soft-tissue tumor components. As with other musculoskeletal neoplasms, accurate assessment of the intra- and extraosseous extent of osteosarcoma is critical in directing limb-salvage procedures. Multiplanar imaging allows assessment of the following vital information: (a) anatomic landmarks for the extent of marrow (Figure 4) and soft-tissue involvement and its relationship to surrounding structures, (b) invasion of the epiphysis, (c) involvement of the joint or neurovascular structures (Figure 3), and (d) identification of areas of viable tumor and mineralized matrix to improve biopsy accuracy (10,12,13,14,15,16,17). The true margins of a lesion, whether intra- or extraosseous, may be obscured by perilesional edema on MR images obtained with water-sensitive pulse sequences (inversion recovery and T2 weighting with fat suppression).

The physis has long been considered by radiologists as a barrier to tumor growth. However, pathologic evaluation has shown that approximately 75% 88% of metaphyseal osteosarcomas extend through the open physis into the epiphysis (Figure 1, Figure 2) (18,19). Epiphyseal extension may be identified at radiography in as few as 17% of osteosarcomas, although this pattern of spread is easily recognized on coronal or sagittal MR images in 80% of metaphyseal osteosarcomas (Figs 1, 2) (9,10,18,19). Joint involvement (most frequently in the knee) can be seen in 19%-24% of osteosarcomas, although the synovium is rarely violated (14). On MR images, joint involvement is suggested when the hyaline cartilage is penetrated or more commonly when tumor extends through the capsule, such as into the suprapatellar bursa anteriorly or posteriorly to encompass the cruciate ligaments (14). Fat-suppressed T1-weighted gadolinium-enhanced images are helpful for delineating extension of tumor into the joint, but enhancing synovium may mimic tumor spread. Although invasion of the joint is unlikely in the absence of an effusion, the presence of an effusion does not allow an accurate prediction of intraarticular invasion.

Treatment of high-grade intramedullary osteosarcoma consists of chemotherapy, followed by wide surgical resection and limb salvage (amputation if salvage is not possible). Clinical outcome of osteosarcoma has dramatically improved over the past 25 years. Currently, the 5-year survival rate is 60%-80% (20,21,22). Tumor size (>10 cm) and advanced stage at presentation are important factors that significantly worsen patient outcome. Evidence of pathologic fracture increases the likelihood of local recurrence. Perhaps the most important determinant of long-term survival of patients with osteosarcoma is tumor response to chemotherapy. Patients with greater than 90% tumor necrosis after therapy have a statistically significant higher likelihood of long-term survival (Figure 4) (20,21,22,23,24,25,26). Ongoing research is being conducted to quantitate the degree of tumor necrosis radiologically by using various modalities including Doppler sonography, bone scintigraphy, and MR imaging (dynamic subtraction studies) before therapy (22,23,24,25,26).

Metastatic disease most commonly affects the lungs, bones, and regional and distant lymph nodes (Figure 5). Ossification of pulmonary and lymph node metastases may be apparent on radiographs, CT scans, MR images, and bone scans (Figure 5). Pulmonary metastases may be associated with spontaneous pneumothorax, and, when few in number, are often treated aggressively with local resection.

Skip metastases, which are foci of tumor within the marrow of the affected bone that are distinctly separate from the primary lesion, occur in 1%-25% of high-grade intramedullary osteosarcomas (Figure 6) (27,28). In our experience, the lower percentage is much more reflective of the true prevalence of this phenomenon. The identification of skip metastases is important not only for defining the extent of disease but also prognostically since the decrement in 5-year survival for patients with skip metastases is similar to that for patients with distant metastatic disease. Skip metastases are best identified with MR imaging, and a study of the entire length of an affected bone should be performed at the time of primary evaluation (Figure 6).

Telangiectatic Osteosarcoma

Telangiectatic osteosarcoma is an uncommon histopathologic subtype that represents 4.5%-11% of all osteosarcomas (1,2,3,4,29,30,31,32,33,34,35,36). Telangiectatic osteosarcoma was first described by Paget (37) in 1854 as a medullary cancer of bone with extensive development of vessels and blood-filled cysts. In 1903, Gaylord (38) used the term malignant bone aneurysm to describe a hemorrhagic, poorly ossified telangiectatic osteosarcoma. In 1922, Ewing (39) was the first to classify telangiectatic osteosarcoma as a distinct histologic variant, characterized by a malignant osteoid-forming sarcoma of bone with large blood-filled vascular channels.

In the largest series to date (124 patients) reported by Huvos and colleagues (30), 60% of the patients with telangiectatic osteosarcoma were male and 40% were female, with an age range of 3-67 years and a mean age of 20 years. The most frequently affected sites were around the knee, representing 62% of cases (48% in the distal femur, 14% in the proximal tibia), with the proximal humerus being the third most frequent site (16% of cases) (30). Similar to conventional osteosarcoma, telangiectatic osteosarcoma uncommonly occurs in the pelvis, scapula, ribs, and skull, and 90% of the lesions are metaphyseal. Telangiectatic osteosarcoma can also be a secondary lesion (arising in association with fibrous dysplasia or Paget disease or following radiation therapy). Two cases of extraskeletal telangiectatic osteosarcoma have also been reported (3,30).

Telangiectatic osteosarcoma must, by definition, have hemorrhagic, cystic, or necrotic spaces (both grossly and microscopically apparent) that occupy more than 90% of the lesion before therapy (Figure 7) (1,2,3,4,30,32). At histologic analysis, the cystic cavities are composed of cavernous vessels and blood-filled spaces lined with osteoclastic giant cells. Viable malignant spindle cells with osteoid formation are seen in the periphery of the lesion and in the septations surrounding these cavities. In larger lesions, areas of bone expansion, cortical destruction, and soft-tissue extension are common.

Telangiectatic osteosarcoma most commonly shows geographic bone destruction with a wide zone of transition (Figure 7a). In our experience, more aggressive osseous involvement with a predominant permeative or moth-eaten pattern is rare, although others have reported that this appearance is the most frequent manifestation (33,36). Marked aneurysmal expansion of bone (Figure 7a) is not infrequent (19% of cases), and metaphyseal lesions often extend into the epiphysis (87%) (33). Aggressive periosteal reaction, cortical destruction, associated soft-tissue mass, and pathologic fracture are common features.

The cystic consistency of telangiectatic osteosarcoma is reflected by its radiologic appearance. Bone scintigraphy often demonstrates peripheral increased radionuclide uptake with central photopenia (donut sign). The CT attenuation of the central portion of the lesion is often lower than that of muscle (Figure 7b). This central region also shows very high signal intensity on T2-weighted MR images. At MR imaging, hemorrhage is frequently observed as areas of high signal intensity, regardless of MR pulse sequence (Figure 7c). Fluid-fluid levels may be seen on CT or MR images, but they are best demonstrated by MR imaging in approximately 90% of cases (33).

The lesion most often confused with telangiectatic osteosarcoma is aneurysmal bone cyst. The most important feature for distinguishing telangiectatic osteosarcoma from aneurysmal bone cyst, in our opinion, is that the former has a rim of viable tumor cells about the cystic spaces that manifests as solid tissue along the lesion periphery and septations. This viable tissue shows enhancement (often nodular) on CT or MR images after intravenous administration of contrast material (Figure 7d). Subtle osteoid formation is also frequently seen in the viable peripheral tumor (intraosseous or soft-tissue component). CT is the best modality for detecting osteoid, which appears as nodular calcific foci. In our recent review of 31 telangiectatic osteosarcomas, these foci were seen on CT scans in 81% of cases, compared with 61% in which they were seen on radiographs (Figure 7b) (33). In our opinion, these features are not seen in aneurysmal bone cyst, which allows distinction from telangiectatic osteosarcoma in most cases.

Treatment of telangiectatic osteosarcoma is similar to that of conventional osteosarcoma and consists of chemotherapy followed by wide surgical resection and limb salvage or amputation. Results of biopsy of these lesions can be misleading if specimens of only hemorrhagic tissue are obtained. Imaging can be helpful in directing the biopsy sampling to the peripheral regions of viable tumor. Prognosis of telangiectatic osteosarcoma was previously thought to be much worse than that of conventional osteosarcoma (32). However, newer studies suggest that the 5-year survival rate of telangiectatic osteosarcoma (68%) is similar to that of conventional osteosarcoma (30,34,35,37).

Low-Grade Intraosseous Osteosarcoma

Low-grade intraosseous osteosarcoma is an unusual variant of conventional osteosarcoma and represents 4%-5% of all lesions; it has also been referred to as well-differentiated or sclerosing osteosarcoma (1,2,3,4,40,41,42,43,44). It occurs most frequently in patients in the 3rd decade of life (1 decade older than conventional osteosarcoma), but patients have a wide age range, and unlike high-grade intramedullary osteosarcoma, men and women are affected equally (40,41,42,43,44). Patients usually present after a protracted clinical course with nonspecific symptoms, but they may be asymptomatic, with the lesion being discovered incidentally. The sites of low-grade intraosseous osteosarcoma are similar to those of conventional osteosarcoma: The femur and tibia (about the knee) are most frequently affected, and the lesion most commonly involves the metaphysis, often with extension into the epiphysis (44).

Unlike conventional osteosarcoma, low-grade intraosseous osteosarcomas frequently have radiologic and pathologic characteristics that simulate a benign process, including fibrous dysplasia, nonossifying fibroma, chondrosarcoma, and chondromyxoid fibroma (38,44). At radiologic examination, the lesion may show well-defined margins, a sclerotic rim, prominent internal trabeculation, and diffuse sclerosis, and it may cause expansile remodeling of bone (Figure 8) (43). However, radiologic evidence of a more aggressive process, such as associated bone lysis, focally indistinct margins, cortical destruction, soft-tissue mass, and, uncommonly, periosteal reaction (Figure 8), is apparent even if it is subtle (43).

Low-grade intraosseous osteosarcoma usually behaves as a locally aggressive tumor, with multiple recurrences developing after intralesional resection. Time to recurrence is variable and can be delayed up to 20 years after surgery (40,44). In general, for those patients whose lesions are initially treated by wide excision with limb salvage, the long-term prognosis is excellent. In 15% of incompletely resected lesions, Kurt et al (44) found transformation of the initial lesion into a higher-grade osteosarcoma, resulting in an increased prevalence of metastatic disease and a poor prognosis. Rarely, low-grade intraosseous osteosarcoma may manifest as a more aggressive tumor with significant metastatic potential.

Small Cell Osteosarcoma

Small cell osteosarcoma is a distinct subtype of conventional osteosarcoma composed of small round blue cells. It was first described by Sim and coworkers in 1979 (45) and is estimated to represent between 1% and 4% of osteosarcomas (1,2,3,4,46,47,48,49,50,51). Males and females are affected equally, and the age distribution of patients and tumor locations are similar to those for conventional osteosarcoma, with the distal femur being the most common site. The lesions are typically metaphyseal with frequent extension into the epiphysis, but 15% of cases involve the diaphysis (45,46,47,48).

The pathologic characteristics of this tumor are similar to those of Ewing sarcoma: Both lesions are composed of small round blue cells. However, small cell osteosarcoma lacks the cellular uniformity seen in Ewing sarcoma and consistently produces osteoid (fine and reticular) (45,48). Ewing sarcoma does not produce osteoid, even though at times reactive bone formation may be encountered and histologic differentiation can be difficult. In this setting, molecular and immunohistochemical markers are very helpful in distinguishing between the two tumors.

At radiologic examination, small cell osteosarcoma typically manifests as a predominantly permeative, lytic medullary lesion with cortical breakthrough, aggressive periosteal reaction, and an associated soft-tissue mass (Figure 9) (45,47,48). Osteoid matrix, although subtle, is usually apparent in the medullary or soft-tissue component and is best detected with CT (Figure 9) (46,48). Occasionally, lesions are entirely lytic with no radiologic evidence of osteoid matrix to suggest the diagnosis of osteosarcoma. The prognosis for patients with small cell osteosarcoma is extremely poor, regardless of treatment.

Osteosarcomatosis

Osteosarcomatosis (also known as multifocal osteosarcoma or multiple sclerotic osteosarcoma) describes a condition in which there are multiple intraosseous foci of osteosarcoma at the time of presentation. Previous investigators have considered osteosarcomatosis to represent multicentric primary neoplasia (52,53,54). More recently, it has been suggested that all cases of osteosarcomatosis represent rapidly progressive metastatic disease (55,56). Although the latter concept is controversial, we strongly endorse it based on the identification of a radiographically dominant (large) lesion in most patients with otherwise symmetric disease and the presence of pulmonary metastases on chest CT scans in the majority of these patients.

Osteosarcomatosis is uncommon, accounting for approximately 3%-4% of osteosarcoma cases (1,2,3,4,52,53,54,55,56,57,58,59). However, multifocal skeletal involvement by osteosarcoma has been found at autopsy in as many as 48% of patients (55,56). Although osteosarcomatosis has been believed to be more common in skeletally immature patients, Hopper et al (56) reported a series of 29 cases in which there were relatively equal numbers of skeletally immature and mature patients. Younger, skeletally immature patients tend to have rapidly appearing, usually symmetric, sclerotic lesions, whereas older patients typically have fewer, asymmetric sclerotic lesions. In 97% of those cases reported by Hopper et al (56), a radiologically dominant skeletal tumor was seen.

The radiologic features of the dominant lesion include ill-defined margins, aggressive periosteal reaction, cortical disruption, and adjacent soft-tissue extension (52,53,54,55,56,57,58,59). Although lesions usually contain cloudlike osteoid (Figure 10), purely lytic dominant lesions may be seen. In contrast to the dominant lesions, the secondary foci are often smaller, more sclerotic, and better defined and lack periosteal reaction or cortical destruction (Figure 10b)

The existence of multifocal skeletal osteosarcoma substantially alters both treatment and anticipated prognosis. In a report on nine patients, Parham et al (59) noted that despite intensive chemotherapy all patients died, with a mean survival of 12 months (range, 6-37 months).

Gnathic Osteosarcoma

Lesions of the mandible and maxilla constitute 6%-9% of all osteosarcomas (1,2,3,4,60,61,62,63,64,65). Gnathic osteosarcoma is often considered a distinct category because of its predilection to affect older patients (average age, 34-36 years) (60,61,62,63,64,65). Lesions affect the alveolar ridge, maxillary antrum, and body of the mandible (Figure 11). At histologic analysis, the lesions are often predominantly chondroblastic (60).

The radiologic appearance of gnathic osteosarcoma is similar to that of conventional osteosarcoma, with evidence of osteoid matrix (60%-80% of cases), aggressive periosteal reaction in mandibular lesions, and soft-tissue extension (100%) (Figure 11) (61,64). Opacification of the maxillary sinuses is also a frequent finding of maxillary lesions. CT is the optimal modality for detecting areas of mineralized osteoid in this complex anatomic location (Figure 11a). MR imaging demonstrates the intramedullary and extraosseous components to best advantage (Figure 11b).

Treatment of gnathic osteosarcoma is difficult and includes radical and local surgical resection, radiation therapy, and chemotherapy. Unfortunately, local recurrence is common (50%-80% of cases), particularly in cases of maxillary lesions, and is often uncontrollable, typically leading to patient death (60,65). Distant metastases are less frequent than in other osteosarcomas, and the 5-year survival rate is approximately 40% (60,65).

Abstract Introduction Primary Intramedullary Osteosarcoma

Surface Osteosarcoma Extraskeletal Osteosarcoma Secondary Osteosarcoma

Conclusions Source Information References