Chondrosarcoma



Chondrosarcoma is a primary malignant tumor of bone in which there is neoplastic differentiation of mesenchymal cells that form chondroid (cartilage-like matrix) without the formation of osteoid (un-mineralized, organic bone matrix). Chondrosarcoma occurs most commonly within bone but can also occur on the surface of bone. 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 juxtacortical chondrosarcoma, which can arise de novo or as the result of a malignant transformation of preexisting osteochondroma.


 

Conventional Chondrosarcoma

Chondrosarcomas are malignant tumors of bone which form cartilage. They designated “primary chondrosarcomas” if they arise in bone without an underlying/preexisting lesion, and they are termed “secondary chondrosarcomas” if they arise in bone with an underlying lesion (e.g., enchondroma). Histologically, chondrosarcomas represent a spectrum of malignancy, ranging from grade 1 chondrosarcoma (low-grade), through grade 2 (intermediate-grade), to grade 3 (high-grade). 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 skeletal sarcomas (second in incidence only to osteosarcomas). They occur equally in both sexes. Chondrosarcoma is primarily a disease of older adults, occurring most commonly in the fifth to seventh decades. Chondrosarcomas 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 can grow quite 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. Chondrosarcoma usually have 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 represents 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 magnetic resonance imaging (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 but also 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 is able to respond to thinning at the endosteal surface with expansion on the periosteal side. This compensatory process leads to an overall widening of bone. Eventually, the cortical side is invaded too and extraosseous extension may occur.

 

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

 

Figure 1: AP radiograph of the right humerus demonstrating grade 2 chondrosarcoma.

 

Figure 2: Axial short tau inversion recovery MRI of the right humerus demonstrating grade 2 chondrosarcoma.

 

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: 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.” Higher grade pathology is characterized by the following changes:

  • increased cellularity,
  • plump nuclei,
  • binucleate cells,
  • more than one cell per lacunar space, and
  • cells outside of lacunar spaces. 

 

With increasing malignancy, there is a gradual and progressive loss of the normal chondroid appearance. Cartilage matrix is replaced by myxoid matrix; there may be generalized loss of matrix as well. The cells become dedifferentiated and the tumor overall becomes hypercellular, with variability in the size and shape of cells and their nuclei (pleiomorphism) with atypia and mitotic figures.

 

In the extreme, 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 doing to the bone based on x-ray and MRI scan images and clinical findings such as pain.

 

Figure 3: H&E stain, benign cartilage.

 

Figure 4: H&E stain, grade 2 chondrosarcoma: Pleiomorphism, atypia, mitotic figures, and myxoid matrix production.

 

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 a chondrosarcoma is a chondroblastic osteosarcoma. A chondroblastic osteosarcoma is a sarcoma that makes both osteoid matrix (the defining feature of an osteosarcoma) and chondroid matrix. (By definition, 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” bur rather “chondroblastic osteosarcoma”.) The distinction between chondroblastic osteosarcoma and chondrosarcoma can often only be made by biopsy.

 

Because chondrosarcomas are typically seen in older patients, the presentation may at first suggest metastatic disease, but this diagnosis would 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 excision. For grade 1 chondrosarcoma, surgical excision is often effective at preventing local recurrence or distant metastasis; five-year survival rates are 90% or higher. For high grade chondrosarcoma, surgical excision is less effective, and, unfortunately, there are no known effective chemotherapy or radiation protocols to treat them.

 


Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a slow-growing tumor, with malignant chondrocytes that show abundant clear cytoplasm and sparse intracellular matrix. Clear cell chondrosarcoma is typically epiphyseal in location and most common in the femoral head.

 

Epidemiology

This is a very rare malignancy that occurs predominantly in patients in their third and fourth decades of life. 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 5).

 

Figure 5: AP radiograph of the right hip demonstrating clear cell chondrosarcoma of the femoral neck.

 

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 6).

 

Figure 6: H&E stain, clear cell chondrosarcoma.

 

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.

 

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.

 


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 low-grade cartilage tumor.

 

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. In light of 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 7 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 7: AP X-ray of the left femur demonstrating dedifferentiated chondrosarcoma.

 

Pathology

The hallmark of dedifferentiated chondrosarcoma is the presence of a high-grade non-chondrosarcomatous tumor immediately juxtaposed to a low-grade cartilage lesion. The high-grade component of the lesion is quite variable and may resemble osteosarcoma, undifferentiated pleomorphic sarcoma, or rhabdomyosarcoma (see Figure 8).

 

Figure 8: H&E stain, dedifferentiated chondrosarcoma.

 

Differential Diagnosis

Radiographically, dedifferentiated chondrosarcoma appears similar to other high-grade bone sarcomas. A specific diagnosis usually requires 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 quite poor. At present, there is no effective drug regimen to treat or prevent metastatic spread, although metastases will occasionally be treated 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.

 

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 9 shows the typical histology of this lesion.

 

Figure 9: H&E stain, mesenchymal chondrosarcoma: Nodules of low-grade cartilage are surrounded by sheets of small round blue cells.

 

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, and this will also be administered to patients with mesenchymal chondrosarcoma if tolerance allows.