Malignant Cartilage Tumors

Definition

Chondrosarcoma can be defined as a malignant tumor of cartilage in which the matrix formed is uniformly and entirely chondroid in nature. This definition is pertinent to all conventional chondrosarcomas irrespective of the site of the tumor. Tumors that exhibit bone-forming capability and the presence of primitive mesenchymal sarcomatous elements in addition to cartilaginous differentiation should not be classified as chondrosarcomas. Such tumors most frequently represent chondroblastic variants of osteosarcoma. The validity of this distinction is confirmed by the observed differences in clinical behavior and therapeutic response between conventional chondrosarcoma and predominantly chondroblastic osteosarcoma. The latter is a tumor that is predominantly cartilaginous in nature but focally shows tumor osteoid being directly produced by sarcomatous cells. It is important to realize that large portions of conventional chondrosarcoma can be composed of calcified tumor matrix, can exhibit myxomatous change, or can show enchondral ossification. The development of ossification in the preexisting cartilage (enchondral ossification) in a conventional chondrosarcoma should not be considered diagnostic of osteosarcoma.

Incidence and Location

Chondrosarcomas represent the second most common group of primary bone sarcomas, and their frequency of occurrence varies in different series from approximately 20% to 27% of all primary bone sarcomas. The most common sites of skeletal involvement and the peak age incidence are shown in Figure 7-2 . The analysis of SEER data indicates that chondrosarcomas represent 25% of all primary sarcomas of bone. The currently available SEER data, which comprise 2757 chondrosarcomas indicates that 74% of them represent conventional chondrosarcomas. The age distribution of patients with chondrosarcoma shows a gradual age-related increase, with the peak incidence occurring during the sixth and seventh decades of life ( Fig. 7-3 ). The majority of patients are older than age 50 years. Chondrosarcomas in people younger than age 45 years are rare. Individual cases are reported in very young patients (age 20 years and younger), but the occurrence of chondrosarcoma in children is very rare. It is therefore recommended that other, more frequent chondroid lesions of bone be ruled out before the diagnosis of chondrosarcoma is rendered in young patients with cartilage tumors. The male-to-female ratio is almost equal. There is no major difference in incidence between black and white subjects ( Fig. 7-4 ). Chondrosarcoma has a predilection for the trunk bones, which are involved in nearly 40% of cases (pelvis ~20% and ribs ~20%) ( Fig. 7-5 ). The ilium is the most frequently involved bone (~20% of all cases), followed by the femur (15%) and humerus (10%). Chondrosarcoma is extremely rare in the spine and craniofacial bones. The majority of cartilage lesions of the small bones of the hands and feet are benign. However, chondrosarcomas do occasionally occur in these acral sites, and it is important to pay close attention to the correlation of clinical and radiologic details in the differential diagnosis between benign and malignant cartilage lesions in these locations. Chondrosarcomas also occur in extraskeletal sites. Chondrosarcomas that occur in soft tissue are typically myxoid and represent a pathogenetically distinct group. A detailed description of extraskeletal chondrosarcoma is beyond the scope of this book. The involvement of laryngeal cartilaginous structures by a chondrosarcoma is a rare but well-recognized feature of these neoplasms. Rare examples of chondrosarcomas in the parenchymal organs most frequently represent divergent cartilaginous differentiation in the sarcomatoid components of epithelial neoplasms. New and unexpected association between breast cancer and chondrosarcoma has been identified by epidemiologic studies of the European cohort. It appears that a subset of estrogen positive breast cancer patients is prone to develop central conventional chondrosarcomas suggesting a putative novel genetic trait distinct from BRCA1 and BRCA2 predisposition.

Clinical Symptoms

Pain is usually the presenting complaint in chondrosarcoma. It is typically described as a dull aching that is sometimes intermittent. The pain is noted at rest and may become severe at night. The symptoms are usually of several months' duration, but it is not uncommon to obtain a history of pain that has continued for several years. If the lesion is located near the end of a bone in proximity to a joint, some restriction of motion can be present. A local swelling may be palpable as a consequence of the expansion of a bone contour or extension into soft tissue. Pain is an important element in the differential diagnosis between malignant and benign cartilage lesions. Benign intramedullary cartilage lesions, such as enchondroma, are typically asymptomatic, and many appear as incidental findings on radiographs.

Radiographic Imaging

The presence of discrete calcified opacities is a radiographic hallmark of cartilage lesions. Typically, the cartilage lesion presents as an area of radiolucency with more or less evenly distributed punctate or ringlike opacities ( Figs. 7-6 and 7-7 ). The level of mineralization may vary from lesion to lesion. At one end of the spectrum are predominantly lytic lesions, and their cartilaginous nature can be difficult to identify radiographically ( Figs. 7-7 to 7-9 ). On the opposite end are heavily calcified lesions with consolidated areas of opacity that can be difficult to distinguish from bone-forming lesions. Typically the lesion appears as a radiolucent area with moderate numbers of punctate opacities, and its cartilaginous nature can be easily recognized on plain radiographs. In the long bones, a large segment of the medullary cavity may be involved ( Fig. 7-7 ). The bone contour in the affected region is at least somewhat expanded. Typically, the cortex is thinned or shows multiple inner surface erosions (endosteal scalloping), but many chondrosarcomas provoke cortical thickening that may be very striking in degree ( Figs. 7-6 and 7-7 ). The outer surface of the cortex overlying the tumor may show a prominent periosteal reaction. This reaction may be in the form of hazy cortical irregularity and fuzziness or of parallel periosteal new bone formation. The multiple perpendicular striations (“sunburst”) often seen in osteosarcoma are usually not present in cartilage lesions. The lesion may have a more or less lobulated contour. Because most chondrosarcomas grow slowly, they do not readily erupt from the bone. Initially, mild expansion of the bone contour is observed with focal thinning of the cortex ( Fig. 7-7 ). An area of complete cortical disruption with an extension into soft tissue is usually present in more advanced lesions. Nearly all lesions of flat bones show features of cortical disruption and significant extension into soft tissue at the time of clinical presentation ( Figs. 7-8 and 7-9 ). The slow growth of chondrosarcoma is associated with a clear radiographic demarcation of the lesion and its low tendency for cortical disruption ( Figs. 7-6 and 7-7 ). Indeed, in long bones, marked thickening of the cortex adjacent to a low-grade chondrosarcoma ( Fig. 7-6 ), which reflects the microscopic permeation of haversian and Volkmann's canals with subsequent bone apposition over a prolonged course, is a definite radiographic indication of malignancy. Early cortical disruption, a destructive (permeative or moth-eaten) pattern of growth, or both features are radiographic signs that indicate a high-grade lesion ( Figs. 7-7 and 7-8 ).

Magentic resonance imaging (MRI) and computed tomography (CT) are indispensable techniques used to evaluate the extent of bone and soft tissue involvement. In addition, MRI typically shows a low signal (signal void) on T1 images and a high signal on T2 images. Although not entirely specific, this feature helps identify the presumptive cartilaginous nature of the lesion in question when the typical pattern of punctate calcification is present on plain radiographs. In addition, CT scans can identify discrete calcifications of the lesion that cannot be resolved on plain radiographs or that are invisible on MRI. This is usually present as punctate signal voids on T1-weighted images.

Gross Findings

In a typical case, the cartilaginous nature of the lesion is readily recognized on gross examination of the bisected tumor. The lesion has a grossly lobulated architecture that is composed of translucent hyaline nodules that, to some extent, resemble normal cartilage ( Figs. 7-10 and 7-11 ). The lobulated nature of the lesion is accentuated by more intense mineralization of the peripheral parts of the lobules. The mineralized areas are opaque, chalklike, or granular and yellow. The presence of extensive enchondral ossification can be grossly identified as focal, ivory-like bony areas in a chondrosarcoma ( Fig. 7-29 ). On the other hand, the tumor may be soft and myxomatous, and hemorrhage or necrosis can be present ( Fig. 7-11 ). The low- to intermediate-grade lesions typically have a grossly recognizable cartilaginous nature, but the central portions of large tumors may become cystic ( Fig. 7-11 ). The presence of gray, friable, and hemorrhagic tissue with a fleshy sarcomatous appearance is indicative of more aggressive high-grade lesions ( Fig. 7-12 ).

In the long tubular bones, large portions of the medullary cavity may be filled with a lobulated cartilaginous tissue. The cortex overlying the affected area is thickened, roughened, and pitted. These features are the result of the slow infiltrative advance of the tumor, with scalloping of the inner cortex and deposition of reactive bone on the outer cortical surface. Initially the lesion grows within the medullary canal, but eventually complete cortical disruption ensues, and the tumor advances through this soft tissue area ( Fig. 7-12 ). Eventually a large lobulated extraosseous mass that is attached to the bone is formed. The extraosseous component often grows on the bone surface, encircling the affected area. Cortical disruption develops earlier in the flat bones, such as the pelvis, scapula, and cranium, which have relatively narrow medullary cavities. Virtually all chondrosarcomas that occur at these sites develop a significant extraosseous component by the time they are clinically symptomatic ( Figs. 7-11 and 7-12 ). In the pelvis, they typically present as sessile lobulated masses with large extraosseous components.

Microscopic Findings

To be classified as a chondrosarcoma, the tumor should be uniformly cartilaginous. The cartilaginous nature of the lesion is typically easy to recognize ( Fig. 7-13 ). The tumor cells resemble normal chondrocytes and lie in lacunar spaces embedded within hyaline cartilage matrix that may be partially calcified or myxoid or that may exhibit foci of enchondral ossification. The level of mineralization can vary in different lesions and in different areas of the same tumor, but typically chondrosarcoma shows mild to moderate levels of calcification. Foci of myxoid change can be present, and some lesions are predominantly myxoid. Chondrosarcoma has an overall lobulated architecture. The individual lobular structures may vary in size, ranging from less than 1 mm to several millimeters in diameter. The individual lobules can be separated by narrow fibrovascular bands. At the periphery, lobules of tumor can be seen permeating the marrow spaces and engulfing cancellous trabeculae of bone ( Figs. 7-14 to 7-16 ). There is usually little or no evidence of reactive bone at the periphery of tumor lobules in the marrow spaces. The lesion can be composed of homogeneous areas of varying size centrally or can have a mixed homogeneous and lobular architecture. Deposition of periosteal new bone can be seen microscopically in areas of complete cortical disruption.

The cells can be more or less uniformly distributed in the cartilaginous matrix or more typically form small clusters ( Figs. 7-17 to 7-19 ). The chondrocyte cytoplasm may show marked multivesicular vacuolization and even ballooning of cells ( Figs. 7-19, 7-21, and 7-23 ). These swollen cells may take on features that suggest clear cell differentiation in chondrosarcoma. However, this finding in an otherwise conventional chondrosarcoma should not be construed as evidence for the diagnosis of the clear cell chondrosarcoma variant. In rare cases, chondrosarcoma exhibits some unusual microscopic features such as the signet-ring appearance or the presence of prominent intranuclear inclusions.

From the diagnostic point of view, chondrosarcomas can be divided into two main groups: low- to intermediate-grade differentiated tumors and high-grade tumors. Those that require supportive evidence other than microscopic features to be definitely classified as chondrosarcomas comprise the group of borderline, low-grade tumors. Those that can be independently identified by microscopic features as malignant cartilage lesions include grade 2 tumors, and those that are frankly anaplastic are grade 3 tumors. Low-grade chondrosarcoma manifests cytologic features similar to those of benign cartilage lesions such as enchondroma. It is important to mention that some benign lesions of cartilage, such as synovial chondromatosis, multiple enchondromatosis (Ollier's disease), and metaplastic cartilage of reactive conditions, may exhibit levels of nuclear atypia and cellularity approximating or even exceeding those of a low-grade chondrosarcoma. Therefore it is mandatory that nuclear atypia and cellularity of the lesion be considered in light of the overall clinical, radiographic, and pathologic patterns of the lesion in question.

In general, a solitary cartilage lesion should be suspected of being a low-grade chondrosarcoma if it shows, even focally, hypercellularity, plump cells with the so-called open nuclear chromatin pattern and prominent nucleoli, the presence of nuclear pleomorphism, and more than occasional double nuclei. As stated, this type of lesion requires clinical and radiologic data to support the diagnosis of chondrosarcoma.

A cartilage lesion should be regarded as chondrosarcoma microscopically if it shows prominent nuclear atypia, mitotic activity with atypical mitoses, and multiple pleomorphic or multinuclear cartilage cells.

Contrary to other bone and soft tissue sarcomas, histologic grading of chondrosarcomas correlates well with their clinical behavior. Chondrosarcomas of different grades most likely represent pathogenetically distinct conditions with different biologic potential and clinical behavior. The most widely accepted method of grading is based on a three-tier system ( Fig. 7-23 ). The diagnostic criteria for the three grades of chondrosarcomas are described next.

Grade 2 Chondrosarcoma.

Grade 2 chondrosarcoma is characterized by a definite and uniformly increased cellularity. The cells can be more or less evenly distributed in the cartilaginous matrix, or they can form loose clusters that vary in size ( Figs. 7-17 to 7-19 ). The cartilage cells are plump and have definitely enlarged nuclei with an open chromatin pattern; distinct nucleoli are present in the majority of cells ( Fig. 7-20 ). Binucleated cells are frequent and occasionally, multinucleated cells with highly atypical nuclei can be seen. Foci of myxoid change are frequently present. Myxoid tumors are classified as grade 2 chondrosarcomas, even when the cellularity of the lesion is relatively low (i.e., similar to that of grade 1 chondrosarcoma) ( Fig. 7-21 ). Grade 2 chondrosarcomas are locally aggressive tumors with a great potential for local recurrence. Approximately 10% to 15% of such tumors metastasize. The most frequent sites of metastasis are lung, regional lymph nodes, and liver. Local recurrence with multiple soft tissue nodules at the site of prior excision is typical for this tumor. The recurrences of grade 1 chondrosarcomas sometimes show an increase in grade sufficient to be classified as grade 2.

Grade 3 Chondrosarcoma.

High-grade chondrosarcomas are rare and make up approximately 5% to 10% of all chondrosarcomas. These tumors are characterized by high cellularity, prominent nuclear atypia, and the presence of mitoses ( Figs. 7-22 and 7-23 ). These features can be uniformly present throughout the tumor or can be seen only focally within a tumor that has overall morphologic features similar to those of grade 2 chondrosarcoma. In general, lesions that are cytologically grade 2 chondrosarcomas and are found to have more than one mitosis per high-power field in focal areas should be classified as grade 3 chondrosarcoma. Grade 3 chondrosarcomas are highly aggressive, rapidly growing lesions with definite metastatic potential. It is estimated that more than 50% of these lesions eventually metastasize. Chondrosarcomas that recur can show an increase in grade. That usually happens in grade 2 lesions, which may recur as grade 3 chondrosarcomas.

Special Techniques

Immunohistochemically chondrosarcoma express markers of cartilage lineage delineation such as SOX9 and S-100 and as such have overlapping immunohistochemical profiles with other cartilage lesions including enchondroma, chondroblastoma, and chondromyxoid fibroma. Therefore, the cartilage lineage expression profile is of minimal use in differential diagnosis of various types of benign and malignant cartilage lesions. It can be of help in those rare instances when the cartilage nature of the tumor in question is not evident on conventional histologic preparations. Chondrosarcoma is usually easy to identify on conventional hematoxylin-eosin–stained sections; immunohistochemical stains are rarely needed to identify the cartilaginous nature of the lesion. Typically S-100 protein is uniformly strongly positive, but in grade 3 lesions, it can be focally negative, especially in less differentiated areas. The issue of coexpression of epithelial markers by some cartilage lesions in the central axis (skull and spine) and their significance for differential diagnosis of chordoma, chondroid chordoma, and chondrosarcoma is discussed in Chapter 18 .

Ultrastructurally, grade 1 chondrosarcomas are similar to enchondromas. The cells of grade 2 chondrosarcomas have enlarged round or oval nuclei with prominent nucleoli. The cytoplasm of cartilage cells shows prominent rough cytoplasmic reticulum, mitochondria, and large amounts of glycogen ( Fig. 7-24 ). Myxoid chondrosarcomas are characterized by the presence of loose granular extracellular matrix and stellate mesenchymal cells ( Fig. 7-25 ). The cytoplasm of these cells has enlarged (dilated) endoplasmic reticulum that forms multiple vacuoles. Grade 3 chondrosarcomas show prominent cellular and nuclear pleomorphism of cartilage cells and focally have undifferentiated mesenchymal cells. Ultrastructural features are of limited value in the differential diagnosis of chondrosarcoma and are almost never required to support the diagnosis.

DNA ploidy measurements have shown that virtually all grade 1 chondrosarcomas are diploid. Conversely, nearly all grade 3 and some grade 2 tumors are aneuploid. Aneuploidy in chondrosarcoma correlates with aggressive clinical behavior (i.e., an increased recurrence rate and high propensity for metastasis). Similarly, an increased proportion of cells in the S phase (>14%) is usually seen in high-grade tumors and correlates with a high propensity for metastases. Some preliminary data suggest that the morphometric analysis of nuclear volume can be helpful in the differential diagnosis of enchondroma versus grade 1 chondrosarcoma.

Chromosomal analysis shows that chondrosarcomas, especially of high histologic grade, have complex aberrations with nonreciprocal translocations and deletions of numerous chromosomes. It appears that rearrangement of 1p and possibly 4, 5, 9, and 20 are nonrandom and may play a role in the biology of these neoplasms. The accumulation of p53 protein that results from the mutation of its coding gene preferentially occurs in the high-grade lesions and may be an indicator of poor prognosis in chondrosarcoma. Loss of heterozygosity (LOH) of 5q, 9p, 11p, 13q, and 19q in chondrosarcoma and chondroblastoma suggest the involvement of genes such as TP53, RB1, CDKN2/p16, ERC, and XRCC in the development of these tumors. Genomic profiling using array comparative hybridization supports the notion that polyploidization of initially hyperhaploid/hypodiploid cell populations is a common mechanism of chondrosarcoma progression. Such studies also suggest the involvement of ribosomal protein S6 and cyclin-dependent kinase 4 in these tumors.

The presence of IDH1 and IDH2 mutations in approximately 50% of central conventional chondrosarcomas suggests the important role of these genes in the development of chondrosarcoma. The identification of similar mutations in solitary enchondromas and the multiple chondromas of Ollier's disease and Maffucci's syndrome as well as periosteal chondromas provides a unifying concept for the pathogenesis of these diverse conditions. Interestingly, similar mutations of IDH1 and IDH2 genes were detected in central nervous system gliomas, acute myelocytic leukemia, and several other solid human tumors. For central nervous system gliomas and acute myelocytic leukemia IDH mutations identify a distinct subset of patients with prognostic implications. No such relationship between IDH mutations and prognosis has been reported for chondrosarcomas. The IDH mutations cause the accumulation of oncometabolite ( R )-2-hydroxyglutarate affecting cell differentiation, survival, and proliferation. A detailed description of IDH biology in cartilage neoplasia is provided in Chapter 6 , in the section describing Ollier's disease.

Several oncogenic pathways affecting the key cellular functions such as migration, cell-stroma interaction, differentiation, and proliferation essential for aggressive behavior of cartilage cells have been implicated in the biology of chondrosarcoma. Integrin activation with upregulation of matrix metalloproteinases and extracellular matrix degradation leading to increased cell migration appears to be dependent on phosphoinositide-3 kinase and MEK-extracellular signal-regulated kinase (ERK) signaling. Additionally, chondrosarcoma cell proliferation and matrix degradation are controlled by peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity. Ephrin-A5 (EFNA5) downregulation is a consistent finding in chondrosarcoma and may contribute to its progression associated with altered cell adhesion. Chondrosarcoma cells are also dependent on such well known regulators of cartilage differentiation and proliferation as hedgehog, p53, insulin-like growth factor, cyclin-dependent kinase 4, hypoxia-inducible factor, SRC, and AKT. All these pathways are implicated as potential therapeutic targets for chondrosarcoma, but no effective targeted therapy is available at the time of this writing.

Differential Diagnosis

Because of its predominantly cartilaginous features, chondroblastic osteosarcoma may be mistaken for chondrosarcoma. This mimicry can lead to the error of underestimating the metastasizing potential of a primary bone sarcoma when small amounts of tumor bone or osteoid formation go undetected because of sampling problems. Careful attention to clinical and radiologic correlation helps prevent these mistakes. Chondrosarcomas are more common in patients beyond the fifth decade of life and are very rare in adolescents. Osteosarcomas with abundant cartilage matrix formation usually show radiologic features more consistent with a bone-forming tumor, including cloudlike radiodensity and prominent periosteal new bone formation in response to cortical disruption. The latter often takes the form of a sunburst or “hair-on-end” appearance that is rarely seen in chondrosarcomas.

Enchondromas and low-grade conventional chondrosarcomas can be almost indistinguishable on cytologic grounds, and attention must be paid to the clinical setting and radiologic response of the surrounding bone, as well as the presence or absence of pain, the age of the patient, and whether the lesion was detected as an incidental finding. The last becomes a factor when asymptomatic enchondromas are discovered only because radiographs are obtained after an injury or bone isotope scans reveal the presence of an undiagnosed central cartilage tumor. Histologically, enchondromas tend to be less cellular, the chondroid matrix tends to be uniformly hyaline, and the matrix calcification may be abundant. The nuclei of the benign cartilage tumor cells are small, uniform, and round and have homogeneous chromatin density, in contrast to the larger nuclei with open chromatin patterns seen in chondrosarcomas. Multinucleation of chondrosarcoma cells is far more frequent than it is in enchondromas. The matrix in chondrosarcomas may show prominent myxoid change, and the tumor tends to infiltrate the intertrabecular spaces and the haversian canals rather than showing the discrete lobules bordered by lamellar bone associated with enchondromas.

The cellular dysplastic cartilage seen in enchondromatosis (Ollier's disease) may present serious problems in the differential diagnosis because of its high cellularity and more frequent binucleation of chondrocytes. The difficulty in distinguishing between enchondromatosis and low-grade chondrosarcoma is further complicated by the fact that highly eccentric dyschrondroplastic lesions and even subperiosteal ones can simulate extraosseous extension of chondrosarcoma. Radiologic demonstration of the typical pattern of polyostotic lesions of Ollier's disease facilitates this distinction.

Fibrous dysplasia with abundant cartilage differentiation (fibrocartilaginous dysplasia) may be difficult to distinguish from chondrosarcoma, particularly with limited biopsy samples having only the cartilage component. The radiographic features of fibrous dysplasia, especially when multiple skeletal sites are affected, offer a good opportunity to make this distinction. The cartilage in a lesion of fibrous dysplasia may also show microscopic evidence of an orderly enchondral ossification sequence that mimics a growth plate. This is usually not found in chondrosarcomas.

Fracture callus and the exuberant reparative changes associated with pubic osteolysis can contain an abundance of proliferating cartilage tissue that sometimes suggests cartilage neoplasia. These can usually be recognized as nonneoplastic conditions when all of the clinical and radiographic data, in addition to the absence of true microscopic anaplasia of the reparative tissue, are considered.

Synovial chondromatosis, particularly when it is associated with bone erosion, has occasionally led to the misdiagnosis of chondrosarcoma. This uncommon situation arises most often in connection with synovial chondromatosis of the hip and of the temporomandibular joint, where extension into bone by cortical erosion occurs more often. Clinical and radiologic suspicion of the synovial origin of the cartilaginous nodular tissue can often be confirmed microscopically.

Conventional Chondrosarcoma in Different Anatomic Sites

Similar to other bone sarcomas, conventional chondrosarcoma has identical microscopic features and biologic potential regardless of its anatomic location. However, it has a unique predilection to involve certain anatomic sites and is extremely rare in some parts of the skeleton. In general, the overall anatomic distribution of chondrosarcoma differs significantly from that of enchondroma, although some overlap exists. Moreover, the clinical significance, technical feasibility of complete removal, and chance for cure differ in relation to the anatomic site. For this reason, separate descriptions of chondrosarcoma and its differential diagnosis in various anatomic sites are provided.

Chondrosarcoma of Ribs and Sternum.

The ribs and sternum are frequent sites (~12% of all cases). Enchondromas at these sites are extremely rare and are typically small, asymptomatic lesions (2 cm in diameter). Chondrosarcomas of the ribs and sternum may occasionally be discovered incidentally on chest radiographs, and the peak age incidence is lower than that for conventional chondrosarcoma at other sites. Typically an expansile lucent lesion is seen with punctate calcifications that are better visualized on CT and MRI ( Figs. 7-26 and 7-27 ). Wide en bloc excision, including of the surrounding chest wall, is required to obtain local control of these tumors. The histologic differentiation is usually grade 1 or 2 in rib and sternal tumors. The clinical differences associated with tumors that arise in this particular location suggest that they may represent a pathogenetically distinct group of chondrosarcomas. For practical purposes, all cartilage lesions of the ribs and sternum with enchondroma-like morphologic features that exceed 2 to 3 cm in diameter should be considered potential chondrosarcomas. Other benign cartilage-containing lesions that should be considered in the differential diagnosis of chondrosarcoma at these sites are cartilage-containing reactive lesions such as fracture callus, fibrous dysplasia with foci of cartilage, and costochondritis. Clinical and radiographic evidence of trauma can be extremely helpful in the differential diagnosis. The periosteal location of the lesion with swelling at the costochondral junction also helps identify the benign reactive process. It should be remembered that fibrous dysplasia is the lesion occurring most frequently in the ribs. In this condition, massive amounts of cartilage may be present. The cartilage can be confused with chondrosarcoma.

Chondrosarcoma of Craniofacial Bones.

Chondrosarcomas of the craniofacial bones are rare (2% of all cases). Typically they occur at the base of the skull ( Fig. 7-28 ), but they may present clinically as orbital, nasal, sinus, or pharyngeal masses. They tend to be histologically of low grade with prominent punctate calcifications best demonstrated on CT or MRI ( Fig. 7-28 ). The cartilage-containing lesions of the maxilla and mandible most frequently represent chondroblastic osteosarcoma rather than true chondrosarcomas. It should be emphasized that in chondroblastic osteosarcoma the cartilaginous component can dominate the lesion, and microscopic evidence of direct osteoid production by sarcomatous tumor cells can be inconspicuous and difficult to document in limited biopsy material. Chondrosarcomas of the base of the skull should also be differentiated from chondroid chordomas. A detailed description of this entity is provided in Chapter 18 . Synovial chondromatosis may involve the temporomandibular joint and can erode the adjacent bone, presenting as a cartilaginous mass at the base of the skull, mimicking a chondrosarcoma.

Chondrosarcoma of Small Bones of Hands and Feet.

The majority of cartilaginous lesions of the small bones of the hands and feet are clinically benign and represent enchondromas. On average, enchondromas in this location are more cellular and have more nuclear atypia than in other parts of the skeleton. Pathologic fractures are often present, and reparative change may complicate the microscopic interpretation of enchondromas. Although very rare (1% of all cases), chondrosarcomas do occur in the acral skeleton ( Figs. 7-29 to 7-31 ). The diagnosis of rare cases of chondrosarcoma distal to wrist and ankle joints is based on strict correlation between the radiographic and pathologic data. A solitary cartilaginous lesion of the acral skeleton should be suspected of being a chondrosarcoma if it shows increased cellularity microscopically with multiple plump cells exhibiting an open nuclear structure and atypia. The cartilage lesions at these sites should be considered chondrosarcomas if an infiltrative destructive growth pattern is documented microscopically and is confirmed by radiographic imaging ( Figs. 7-30 and 7-31 ).

Treatment and Behavior

The successful eradication of a malignant cartilage tumor depends on complete wide excision, if this is technically feasible. Surgery is the primary and most effective treatment for chondrosarcoma. Other modalities, such as irradiation and chemotherapy, play a minor role and only apply to high-grade chondrosarcomas. Consequently the lesions located in anatomic sites where wide local excision is technically possible have better prognoses than those located at sites where complete removal is not possible. The overall prognosis is related to the size of the lesion, anatomic location, and histologic grade. In general, lesions of the appendicular skeleton have better prognoses than those of the axial skeleton. Data from the University of Texas M.D. Anderson Cancer Center indicate that the survival rate is strictly related to the histologic grade of the tumor, with 5-year survival rates of 90% for grade 1, 81% for grade 2, and 29% for grade 3 tumors. It is evident that the most significant difference in clinical behavior is between grade 2 and 3 chondrosarcomas. Grade 1 and 2 lesions behave clinically in a somewhat similar manner. The overall 5-year survival rate varies between 48% and 60%. Recurrences in chondrosarcoma typically occur 5 to 10 years or more after surgery. In some instances, recurrence can be associated with an increase in histologic grade and more aggressive clinical behavior than that of the primary neoplasm. Distant metastases are most often observed in grade 3 chondrosarcoma (66%), and the lungs are the most frequent site. Grade 2 lesions sometimes give rise to distant metastases (10%). Chondrosarcoma metastasizes to the lymph nodes more frequently than other bone sarcomas. Other less frequent sites of metastasis are the liver, kidneys, and brain. Grade 1 chondrosarcomas do not metastasize, but a fatal outcome in 10% of cases results from local uncontrollable growth. In addition, in rare cases, low-grade chondrosarcoma can recur as a high-grade pleomorphic (dedifferentiated) neoplasm. Although remote, the possibility of dedifferentiation should be considered if conservative management of a cartilage lesion is planned.

Tumors that are not amenable to complete excision because of their location, such as the skull base, are treated by conventional radiotherapy for limited local control in the postoperative setting or in advanced inoperable cases with definitive intent. The use of proton therapy after maximal surgical resection in such locations offers increased probability of a long-term cure with relatively low risk of significant complications.

Personal Comments

The most common diagnostic problem in chondrosarcoma is the evaluation of an intramedullary cartilage tumor, most often in a long bone of an extremity that shows equivocal histologic features and is borderline in size. The presence of radiologic changes in the adjacent cortex and surrounding cancellous bone and the clinical history regarding the events that led to the discovery of the cartilage lesion are of paramount importance in the recognition of a low-grade chondrosarcoma. The widespread use of radioisotope scanning with bone-seeking isotopes and MRI, both of which are extremely sensitive in demonstrating focally increased mineral turnover and marrow alterations produced by small asymptomatic lesions, have led to more frequent identification of cartilage tumors. The use of these techniques has multiplied the frequency with which these cartilaginous masses must be evaluated histologically. In general, a borderline lesion should be suspected to be a chondrosarcoma if radiologically it provokes a sclerotic reaction with thickening of the adjacent cortex, if there is an alteration in the trabecular pattern in the surrounding cancellous bone (usually loss of trabeculae), and if there is associated pain, particularly at rest. Enchondromas can certainly produce endosteal scalloping in the adjacent cortex, especially in small tubular bones, but in large lesions of long bones, this must always be regarded as a radiologic sign of growth.

In enchondromatosis (Ollier's disease), the recognition of secondary malignant change may be extremely difficult if the pathologist is not familiar with the spectrum of radiologic appearances of this disorder because the diagnosis of secondary malignancy often cannot be based on histologic criteria alone. This results from the fact that in Ollier's disease, the dysplastic cartilage can be highly cellular and show mild to moderate atypia and prominent myxoid changes. Extension of cellular cartilaginous tissue into the adjacent soft tissue and a clinical history of a newly discovered mass and associated pain are the most consistent signals of malignant transformation.

Synovial chondromatosis is a lesion of soft tissue or joints that offers many interpretive pitfalls to the unsuspecting pathologist, particularly when it involves unusual sites, such as the temporomandibular joint and spinal facet joints. Prominent nuclear pleomorphism and chondrocyte multinucleation should not be regarded as evidence of malignancy in this synovial metaplastic condition. When bone erosion occurs in long-standing synovial chondromatosis, it can be mistaken for chondrosarcoma. In these cases, it is essential to look for the presence of affected synovium to distinguish this lesion from chondrosarcoma.

Chondrosarcoma also may be mimicked in two other nonneoplastic conditions: pubic osteolysis and tophaceous pseudogout. In bulky soft tissue deposits of calcium pyrophosphate dihydrate (pseudogout), erosion into bone (hip joint, temporomandibular joint) can occur, and the chondroid metaplasia frequently found in the connective tissue surrounding the tophaceous pseudogout deposit can be misinterpreted as chondrosarcoma. This error can be avoided by the recognition of the specific nature of the pseudogout crystalline deposit, which is not seen in the calcifications of chondrosarcoma.

Pubic osteolysis is a reparative nonneoplastic condition that is often rich in cellular cartilage associated with pelvic insufficiency fractures. When the fracture callus produces a significant soft tissue mass, it can raise suspicion of a pubic chondrosarcoma. If a pathologist is presented with a small biopsy sample from such a mass, it is all too easy to make an erroneous diagnosis of chondrosarcoma unless radiologic correlation is pursued scrupulously.

Cartilaginous lesions of the testes, ovaries, and peritoneal or mediastinal soft parts are typically teratomatous in nature. In such instances, meticulous search for other components of germ cell neoplasia is advised before the lesion is classified as chondrosarcoma in these unusual sites.