Malignant Cartilage Tumors
Chondrosarcoma is the second most frequent primary malignant tumor of bone. It represents one fourth of all primary bone sarcomas. The term chondrosarcoma is used to describe a heterogeneous group of lesions with diverse morphologic features and clinical behavior. The behavior of these lesions ranges from slowly growing, nonmetastasizing tumors to very aggressive metastasizing sarcomas. More than 90% of these tumors are designated as conventional chondrosarcomas. On the basis of histologic features (nuclear atypia and cellularity), conventional chondrosarcoma is further subdivided into three grades, 1 through 3, which correlate well with their clinical behavior. The majority of conventional chondrosarcomas are low- to intermediate-grade tumors that have indolent clinical behavior and low metastatic potential. High-grade (grade 3) tumors are less frequent and have high metastatic potential.27,38 The current analysis of data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program comprising 2048 conventional chondrosarcomas indicates that 80% of them represent low-grade to intermediate-grade (grade 1 or 2) lesions and the remaining 20% are classified as high-grade (grade 3), potentially aggressive tumors.
The fundamental biologic difference between a grade 1 chondrosarcoma and a benign enchondroma is signified by the limited growth potential of the enchondroma and the slow but continuous locally invasive growth of a low-grade chondrosarcoma. A distinction between these two conditions solely on the basis of microscopic cytologic details is often impossible. Therefore the pathologist should consider other data, such as clinical presentation and radiographic features, in arriving at a diagnosis. For example, it is known that cartilage lesions involving some parts of the skeleton (small bones of the hands and feet) are almost always benign, whereas cartilaginous lesions of the ribs, sternum, and flat bones such as the pelvis and scapula frequently behave in a clinically aggressive manner. On the microscopic level, the pattern of growth and the relationship of the lesion to adjacent structures should also be taken into consideration. All these data are used to provide clues about the biologic potential of the lesion in question and about the lesion’s ultimate clinical behavior. Virtually all de novo chondrosarcomas of bone are intramedullary lesions. Primary juxtacortical (surface) chondrosarcomas are extremely rare, but malignant change is a known secondary complication of osteochondromas. Secondary chondrosarcomas that complicate other conditions (e.g., in Ollier’s disease) are morphologically similar to conventional chondrosarcoma, but they form a distinct group of lesions and are defined by the clinical setting in which they occur. They provide useful models in which to study the factors (clinical, pathologic, and molecular) that predispose to the development of malignant lesions of cartilage. The special types of chondrosarcomas include dedifferentiated, mesenchymal, and clear-cell chondrosarcomas. These tumors have distinct morphologic features and clinical behaviors and should be considered as entities separate from conventional chondrosarcoma. The differences in the biologic potential of cartilage lesions as related to their degree of differentiation are provided in Figure 7-1.
Intramedullary Chondrosarcoma
Conventional Chondrosarcoma
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.6,27,35,38 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.46,98 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.18,35,39,80 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.24,44,75,78,79 Rare examples of chondrosarcomas in the parenchymal organs most frequently represent divergent cartilaginous differentiation in the sarcomatoid components of epithelial neoplasms.16,66 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.20,68
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.8,17,21,45,76 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.32,36 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.25,29,47
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.17,21,29,33,34,72,76,83
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.6,8,10,17,31,35,37,42,58,64,81,82 Chondrosarcomas of different grades most likely represent pathogenetically distinct conditions with different biologic potential and clinical behavior.58–60,96 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 1 Chondrosarcoma.
Grade 1 chondrosarcoma is cytologically very similar to enchondroma. The microscopic differences are minimal, and the distinction may be a subjective one.21,29,33,37,49 Overall the cellularity is higher than in enchondroma, and there are more than occasional plump nuclei with an open chromatin structure and double nuclei (Fig. 7-13). The lesion typically has an infiltrative growth pattern with features of endosteal erosion and engulfment of the adjacent cancellous bone. Clinical and radiologic features of extraosseous extension can be present. The pattern of growth and the relationship of the lesion to the adjacent bone and soft tissue often cannot be evaluated in limited biopsy material. The diagnosis of grade 1 chondrosarcoma nearly always requires supportive evidence from the clinical and radiographic data. For example, lesions in certain anatomic locations, such as the ribs, sternum, and flat bones, nearly always behave in an aggressive manner. By contrast, cartilage lesions located distal to the wrist and ankle joints are nearly always clinically benign. However, it must be mentioned that enchondromas do occur in the axial skeleton, and well-documented examples of benign cartilage lesions in the ribs, sternum, and flat bones have also been reported. Pain is an important symptom of cartilage malignancy and is believed to be related to an infiltrative growth pattern. Radiographic data are indispensable in the evaluation of cartilage lesions. The large size of the mass indicates a continuous growth potential and a clinically aggressive lesion. Radiographic evidence of bone contour expansion, cortical thinning, endosteal scalloping, and the presence of solid periosteal new bone formation with cortical thickening in the vicinity of the tumor all indicate a clinically aggressive lesion.43 Grade 1 chondrosarcoma is a slowly growing, locally aggressive tumor with an indolent course and recurrent growth potential. Metastatic spread is not a feature of grade 1 chondrosarcoma, but uncontrolled local recurrence can lead to a fatal outcome.
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