Chondrosarcoma

Chondrosarcoma is a primary malignant tumor of bone in which there is neoplastic differentiation of mesenchymal cells forming chondroid matrix. Chondrosarcoma occurs most commonly within bone, but can also occur on the surface of a bone and rarely in soft tissue. Major chondrosarcoma variants include conventional chondrosarcoma, clear cell chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma. There is also a variant of chondrosarcoma that occurs on the surface of bone, termed periosteal chondrosarcoma. This entity was previously known as juxtacortical chondrosarcoma.

Conventional Chondrosarcoma

Chondrosarcomas are malignant tumors of bone which form cartilage. They are designated “primary chondrosarcomas” if they arise in bone without an underlying/preexisting lesion, and they are termed “secondary chondrosarcomas” if they arise in bone within an underlying lesion (e.g., with an enchondroma). Histologically, chondrosarcomas represent a spectrum of malignancy, ranging from grade 1 chondrosarcoma (low grade), through grade 2 (intermediate grade), to grade 3 (both high grade and dedifferentiated). The clinical aggressiveness of chondrosarcomas is related to both the histologic grade of the tumor and the size of the lesion.

Epidemiology

Chondrosarcomas account for 20% of all primary malignant bone tumors, second in incidence only to osteosarcomas. Chondrosarcomas are primarily a disease of older adults, occurring most commonly in the fifth to seventh decades and are rare in individuals under the age of 20.

Clinical Features

The most common locations for chondrosarcomas are the proximal and distal femur, pelvis, and humerus. When found in long bones, chondrosarcomas tend to be diaphyseal or metaphyseal in location. The most common presenting symptom is pain – a non-specific symptom, which early on can mimic other non-neoplastic conditions. Night pain should raise the suspicion of an underlying tumor but can also occur with degenerative conditions. Grade 1 and 2 chondrosarcomas tend to be fairly slow growing, whereas grade 3 and dedifferentiated can grow rapidly. It is not uncommon for chondrosarcomas to also present with a mass once extraosseous extension is present.

Radiologic Features

The hallmark of a conventional chondrosarcoma radiographically is chondroid calcification and aggressive destruction of the bone within which it is located. A chondrosarcoma usually has a core of intralesional lysis surrounded by endosteal scalloping and cortical thinning and expansion. Intralesional lysis refers to a relatively lytic area within a more calcified area of intramedullary cartilage; the lytic area may represent a newer, more active region of cartilaginous growth that has not been present long enough to become calcified. More aggressive, higher-grade lesions may demonstrate gross cortical destruction and extraosseous extension.

The vast majority (~85%) of central chondrosarcomas are either grade 1 or 2. Cartilage tumors are typically lobular in shape. For a completely intraosseous lesion, this shape may be obvious on plain x-ray and more so on CT or MRI. As these tumors grow, they eventually encounter an adjacent cortex. Their growth against the endosteum of that cortex compresses the lobar shape of the tumor into the adjacent cortex as it erodes into the endosteum, giving it a scalloped appearance. The scallops formed by malignant cartilage tumors are typically each greater than 1 cm in size. As these tumors continue to grow, they cause progressive cortical resorption on the endosteal surface. Because lower-grade lesions grow slowly, the cortical bone responds by thinning at the endosteal surface with expansion and subsequent new bone formation on the periosteal side. This compensatory process leads to an overall widening of the bone. Eventually, the cortical side is eroded and extraosseous extension can occur.

Matrix calcification visible on CT in 94% of cases and cortical breach in approximately 90% of long-bone chondrosarcomas.

The typical appearance of a central chondrosarcoma with chondroid calcification, intra-lesional lysis, endosteal scalloping, and cortical thinning and expansion is shown in Figures 1 and 2.

Figure 1: AP radiograph of the right humerus demonstrating a grade 2 chondrosarcoma with soft tissue extension.

Figure 2: Axial short tau inversion recovery (STIR) MRI of the right humerus demonstrating a grade 2 chondrosarcoma with an extensive lobular soft tissue mass.

Pathology

Unlike most other bone sarcomas, cartilage tumors occur as a continuum from benign to low-grade, intermediate-grade, and high-grade malignancies, with no abrupt line of demarcation between them.

Benign cartilage tumors have hypocellular hyaline cartilage with one cell per lacunar space. The chondrocytes have small eccentric, crescent-shaped nuclei found in a sea of abundant, uniform, high-quality chondroid matrix (Figure 3). These characteristics are collectively termed “benign-appearing hyaline cartilage.” Borderline low-grade pathology is characterized by the following changes which occur in the context of the continued presence of high quality chondroid matrix: increased cellularity; plump nuclei; binucleate cells; more than one cell per lacunar space; and cells outside of lacunar spaces.

Figure 3: H&E stain, benign cartilage demonstrating hypocellularity with cells in lacunae with small nuclei and uniform chondroid matrix. (courtesy Dr. Gord Zhu)

Figure 4: H&E stain, grade 2 chondrosarcoma: Pleomorphism, atypia, mitotic figures, and myxoid matrix production. (courtesy Dr. Gord Zhu)

The distinction from enchondroma often depends on demonstrating infiltration through the marrow cavity rather than confinement by native architecture.

With increasing malignancy, there is a gradual and progressive loss of the normal chondroid appearance as tumors of progressively higher grade lose more and more of their normal chondroid phenotype. Cartilage matrix shows an increasingly poor quality, described as myxoid change and there may be generalized loss of matrix as well in higher grade lesions. The cells become dedifferentiated with large plump nuclei replacing small crescent-shaped nuclei. The tumor overall becomes hypercellular, with variability in the size and shape of cells and their nuclei (pleomorphism). They also progressively demonstrate atypia and mitotic figures with less prominent chondroid matrix as the tumor gradually loses its normal chondroid phenotype.

Intermediate to high-grade chondrosarcomas are markedly different in appearance compared to benign lesions, and thus fairly easy to diagnose histologically. Diagnosing low-grade lesions, however, is much more challenging, as the differences compared to normal may be subtle. As such, cartilage lesions need to be defined not only by their histologic appearance, but also by their radiographic and clinical findings. In the case of very low-grade histologic lesions, x-ray and MRI scan may reveal more about the aggressive nature of a lesion than the histology itself. While it is difficult for pathologists to predict the behavior of low-grade lesions, it is easier to see what these lesions are actually doing to the bone based on x-ray and MRI scan images and clinical findings such as pain. Again, this leads pathologists to lump these borderline lesions into the category “low-grade cartilage tumor” and leave treatment or follow-up decisions to the clinician.

Differential Diagnosis

It is possible to confuse a central cartilage tumor with a bone infarct. Also, because chondrosarcomas can demonstrate areas of calcification, another item on the differential diagnosis of chondrosarcoma is chondroblastic osteosarcoma. A chondroblastic osteosarcoma is a sarcoma that makes both osteoid matrix (the defining feature of an osteosarcoma) and chondroid matrix. Any malignant tumor that forms osteoid is defined as an osteosarcoma, even if the osteoid production comprises only a small portion of the tumor. Thus, a combined lesion is not called an “osteoblastic chondrosarcoma,” but rather a “chondroblastic osteosarcoma”. The distinction between chondroblastic osteosarcoma and chondrosarcoma can only be definitively made by biopsy. Because chondrosarcomas are typically seen in older patients, the presentation may at first suggest metastatic disease, but this diagnosis should be clarified by biopsy.

Disease Course: Treatment and Prognosis

While low-grade chondrosarcomas are typically limited to localized disease, high-grade chondrosarcomas have a propensity for metastatic spread and are thus associated with a high mortality risk.

The primary treatment for all grades of chondrosarcoma is wide surgical resection. For grade 1 chondrosarcoma, intralesional surgical excision is often effective at preventing local recurrence and five-year survival rates can exceed 90%. Metastasis rates are less than 10% for low-grade, 10–50% for intermediate, and 50–70% for high-grade. Unfortunately, there are no known effective chemotherapy or radiation protocols to treat grade 2 or 3 chondrosarcoma or their metastases. For intermediate and high grade chondrosarcoma, wide surgical resection with negative margins is effective for local control but cannot prevent the appearance of distant metastases. Survival rates are 60–70% for grade 2 and 30–50% for grade 3.

Dedifferentiated Chondrosarcoma

Dedifferentiated chondrosarcoma is defined as a tumor composed of a high-grade, non-chondrosarcomatous tumor, such as osteosarcoma, undifferentiated pleomorphic sarcoma, or rhabdomyosarcoma, in association with a lower-grade chondrosarcoma.

Epidemiology

Dedifferentiated chondrosarcoma is a very rare malignant tumor of bone that occurs most commonly in patients greater than 50 years old.

Clinical Features

As with most chondrosarcomas, dedifferentiated chondrosarcoma is typically metaphyseal or diaphyseal. Pain is the most common presenting symptom. Because of its extremely high-grade nature and aggressive behavior, pathologic fracture is also common as a presenting symptom.

Radiologic Features

Dedifferentiated chondrosarcoma appears as a typical high-grade lesion with gross bone destruction. Because of its very high-grade malignant nature, this tumor commonly presents with soft-tissue extension adjacent to its bone of origin. Considering the biphasic nature of its histology, radiographic findings may also demonstrate the appearance of a low-grade cartilage tumor juxtaposed to a non-chondroid, aggressive lesion. Figure 5 demonstrates a benign appearing enchondroma in the distal shaft of the left femur beside a lytic and destructive lesion that represents the high-grade dedifferentiated component.

Figure 5: AP X-ray of the left femur demonstrating a dedifferentiated chondrosarcoma. Note the preexisting calcified enchondroma proximally, and the more distal intralesional lysis and cortical destruction.

Pathology

The hallmark of dedifferentiated chondrosarcoma is the presence of a high-grade non-chondrosarcomatous tumor immediately juxtaposed to a lower-grade cartilage lesion. The high-grade component of the lesion is variable and may resemble osteosarcoma, undifferentiated pleomorphic sarcoma, or rhabdomyosarcoma (see Figure 6).

Figure 6: H&E stain of dedifferentiated chondrosarcoma: It is characterized by sharp interface between the low-grade conventional chondrosarcoma on the left side and high grade non-cartilaginous sarcoma (dedifferentiated) components on the right side. The high-grade non-cartilaginous component demonstrates undifferentiated pleomorphic sarcoma morphology, with marked cellularity, pleomorphism, and brisk mitotic activity. (courtesy Dr. Gord Zhu)

Differential Diagnosis

Radiographically, dedifferentiated chondrosarcoma appears similar to other high-grade bone sarcomas. A specific diagnosis usually requires biopsy for histologic confirmation.

Disease Course: Treatment and Prognosis

Dedifferentiated chondrosarcomas are managed in a similar fashion to other high-grade bone sarcomas. The hallmark of local treatment is wide-margin surgical resection. Systemic metastases are exceedingly common, and the overall prognosis for these patients is poor; 5-year survival is below 20%. At present, there is no effective drug regimen to treat or prevent metastatic spread, although metastases will occasionally be addressed with systemic treatment effective against the histologic subtype of the dedifferentiated area.

Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is an extremely rare high-grade chondrosarcoma subtype defined by the presence of sheets of small round to oval cells in association with low-grade malignant cartilage lesion.

Epidemiology

Mesenchymal chondrosarcoma is a rare lesion, and when found, tends to occur in younger adults, typically below the age of 40. Most common skeletal locations include the pelvis, femur, ribs, and vertebrae.

Clinical and Radiologic Features

Clinical and radiologic features of mesenchymal chondrosarcoma are similar to that of dedifferentiated chondrosarcoma.

Pathology

Histologic examination of mesenchymal chondrosarcoma typically reveals sheets of small round blue cells immediately juxtaposed to areas of low-grade cartilage. Figure 7 shows the typical histology of this lesion.

Figure 7: H&E stain, mesenchymal chondrosarcoma. Nodules of low-grade cartilage (seen in the lower right portion of this slide) are surrounded by sheets of small round blue cells. (Courtesy of Dr. Gord Zhu.)

Disease Course: Treatment and Prognosis

Treatment and prognosis of mesenchymal chondrosarcoma are similar to dedifferentiated chondrosarcoma. The small round blue cell component of this tumor is sensitive to chemotherapy regimens administered to Ewing sarcoma patients. This will be administered to patients with mesenchymal chondrosarcoma if the patient can tolerate it. Even then, these tumors generally have a poor prognosis.

Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a rare, slow-growing tumor, with malignant chondrocytes that show abundant clear cytoplasm and sparse intracellular matrix. This histologic picture has been described as a “fried egg” appearance. Clear cell chondrosarcoma is typically epiphyseal in location and most common in the femoral head. Treatment is wide surgical excision.

Epidemiology

This is a very rare sarcoma which occurs predominantly in patients in their third and fourth decades and is most common in the femoral head. It typically demonstrates low-grade biological potential.

Clinical Features

Because of the epiphyseal location, patients typically present with joint complaints such as pain, stiffness, and decreased range of motion.

Radiologic Features

Radiographic imaging demonstrates a lytic, intra-epiphyseal lesion with geographic lysis and focal chondroid calcification (figure 8).

Figure 8: AP radiograph of the pelvis and hips showing a lytic lesion with subtle chondroid calcifications in the femoral head. The margins are ill-defined, with no surrounding sclerosis and no cortical breakthrough or articular collapse, features consistent with clear cell chondrosarcoma.

Pathology

The dominant cell in this tumor is a clear cell chondrocyte, whose appearance has been described as a “fried egg.” These cells are well-demarcated and associated with a sparse chondroid matrix.

Figure 9: Sheets and nests of clear cells with abundant clear cytoplasm, well-defined cell borders, and centrally placed hyperchromatic nuclei are characteristic of clear cell chondrosarcoma. Osteoclast-type giant cells are present at the periphery along woven bone trabeculae within a chondroid matrix.

Differential Diagnosis

While these tumors do have a typical radiographic appearance, they can mimic changes seen with avascular necrosis of the femoral head or those associated with a femoral head fracture. They may also appear similar to other epiphyseal tumors in adults such as giant cell tumor of bone.

Disease Course: Treatment and Prognosis

Since most of these tumors demonstrate low-grade biologic behavior, wide-margin surgery is the standard treatment. No systemic treatment is currently available. Local recurrence and occasional regional or distant metastases may occur and have been reported up to 15-20 years following initial treatment.

Key Test Topics

Chondrosarcoma is a malignant tumor of cartilage characterized radiographically by chondroid calcification with intralesional lysis, endosteal scalloping, and cortical expansion or destruction.
Low grade lesions may be difficult to differentiate from enchondroma on pathology and imaging features of aggressiveness often drive treatment.
Clear cell chondrosarcoma occurs most commonly in the femoral head in a skeletally mature individual.
Wide surgical resection is the treatment for grade 2 or higher lesions, while grade 1 lesions can undergo intralesional curettage. There is no defined role for chemotherapy or radiation in the treatment of these tumors.