Traditionally, cartilage lesions are considered to be of neoplastic, dysplastic, hamartomatous, and reactive origin. Reactive cartilage containing lesions are described in Chapters 20 and 23. Enchondroma is an example of a benign cartilage neoplasm that most frequently occurs within the medullary cavity. It rarely presents as a bone surface subperiosteal (juxtacortical) lesion such as a periosteal chondroma. Enchondromatosis is considered to represent a dysplastic cartilage condition rather than a true neoplasm. It occurs in two main clinical settings: Ollier’s disease and Maffucci’s syndrome. Although solitary enchondromas and enchondromatosis in Ollier’s disease and Maffucci’s syndrome are clinically distinct, they share similar genetic abnormalities with frequent mutations of IDH1 and IDH2 genes. More recent experience discloses the heterogeneous nature of enchondromatosis, which, in addition to Ollier’s disease and Maffucci’s syndrome, can be separated into at least five unique clinical syndromes with different patterns of skeletal involvement, genetic background, and means of familial transmission. Chondroblastomas and chondromyxoid fibromas are two examples of benign cartilage neoplasms that are characterized by immature cartilage cells and an extracellular matrix component. Osteochondroma, or osteocartilaginous exostosis, is traditionally presented as a developmental anomaly of the hamartomatous type. The most frequent expression is a solitary exostosis. The less frequent form is a clinical syndrome of multiple hereditary exostosis in which osteochondromas are associated with other anomalies of skeletal modeling. In view of recent identification of unique genetic abnormalities characterized by the silencing of EXT1 and EXT2 genes in both forms of the disease, the traditional hamartomatous concept has to be revisited and an osteochondroma is better described as a unique benign neoplasm recapitulating epiphyseal skeletal development. Some of the benign cartilage lesions are precursor lesions for malignant neoplasms. Although this chapter deals with benign cartilage lesions, secondary bone sarcomas developing in association with some preexisting benign cartilage lesions are also discussed.
Enchondroma is a common intramedullary benign neoplasm composed of mature cartilage. It has a limited growth potential, and a majority of enchondromas are small, asymptomatic lesions less than 3 cm in diameter.
Incidence and Location
Enchondroma is a frequently occurring benign tumor that, in different series, accounts for 12% to 24% of benign bone tumors and 3% to 10% of all bone tumors. The age of patients varies widely, and in some series, enchondromas are fairly evenly distributed throughout all decades of life.5 In other series, the peak age incidence seems to be during the third and fourth decades of life. More than 60% of patients are age 10 to 40 years.7,10,29,30 There is no clear sex predilection, and the male-to-female sex ratio is about 1 : 1. The small bones of the hands and feet are the most frequent anatomic sites for enchondroma, and approximately 60% of cases are located in these sites. The small bones of the hands are more frequently involved than the bones of the feet (ratio approximately 7 : 1). Involvement of the long tubular bones is next in frequency. The femur is the most frequently involved long tubular bone and makes up approximately 17% of all cases. Enchondromas of the femur are typically located near the proximal or distal ends. Midshaft involvement is very rare. The proximal humerus is involved in approximately 7% of cases. Enchondromas occur less commonly in the bones of the forearm, tibia, and fibula. They are very rare in the pelvis, ribs, scapulae, and vertebrae. Moreover, in several major series of bone tumors, there is not a single report of an enchondroma in the craniofacial bones. In general, enchondromas are extremely rare in the sites most commonly affected by chondrosarcoma: the trunk bones. To the contrary, they occur frequently in the acral skeleton, where chondrosarcomas almost never occur. The site where significant overlap between the skeletal distribution of enchondroma and chondrosarcoma occurs is in the long tubular bones, where both lesions occur with similar frequency. The peak age incidence and most common sites of enchondroma are depicted in Figure 6-1.
Typically, enchondroma is an asymptomatic lesion incidentally discovered on radiographs or radioisotope scans performed for other reasons. In the small bones of the hands and feet, an enchondroma can expand the bone contour and present as a palpable mass. Pathologic fracture can be the presenting sign of enchondroma in phalanges, metacarpals, and metatarsal bones. Pain in cartilage lesions often correlates with growth activity. Therefore, if such growth cannot be explained by recent injury, pathologic fracture, or the presence of other unrelated conditions, pain should raise the suspicion of malignancy.
Enchondroma produces a localized, radiolucent defect with punctate or less frequently linear calcifications (see Figs. 6-2 to 6-5). Whether the lesion is sharply defined or has indefinite outlines within bone depends on the skeletal site. The degree of radiographic calcification can vary considerably. Occasionally, there may not be a sufficient amount of mineralization to be detected on plain radiographs, and the lesion can be purely lytic in appearance (see Figs. 6-6 and 6-7). In some radiolucent lesions, computed tomographic (CT) imaging may reveal the presence of calcifications. On magnetic resonance imaging (MRI), calcifications appear as small signal voids. MRI is better suited to demonstrate the noncalcified chondroid lesions within the marrow cavity as a low-signal–intensive area on T1-weighted images and a high-signal–intensive area on T2-weighted images (see Figs. 6-2 to 6-5). In the major long bones, the cortex and bone contour are usually not altered, and there is no periosteal new bone formation (see Figs. 6-2 to 6-6). Enchondromas that fill the medullary cavity of short tubular bones may show some cortical thinning (see Figs. 6-6 and 6-7). The contour of the small bones is typically expanded along with cortical thinning. Radiographic evidence of true extension into soft tissue with a completely disrupted cortex, as well as the presence of reactive periosteal new bone formation, should be regarded as indicators of malignancy. In rare cases, eccentric expansion of one cortex can produce the picture of enchondroma protuberans (Fig. 6-8).4,5,8 In the small tubular bones, the lesion is usually diaphyseal, but epiphyseal extension is also frequently present. In the long tubular bones, enchondromas are most frequently located in the metaphysis. A midshaft or epiphyseal localization is extremely uncommon (see Figs. 6-6 and 6-7).22 In the long bones, enchondromas typically do not show distinct outlines on plain radiographs as they tend to do in short tubular bones. On the other hand, MRIs demonstrate their sharply defined, often lobulated borders (see Figs. 6-2 to 6-5).
Although curettage specimen material is the rule, in the occasionally received intact resection specimen the cartilaginous nature of the lesion is easy to recognize on gross examination (Figs. 6-9 and 6-10). Enchondroma is composed of confluent lobules of cartilage. The lobules vary in size from less than 1 mm through several millimeters to more than 1 cm. The periphery of the lesion is often somewhat irregular because the individual lobules can bulge into the adjacent marrow spaces or separate satellite foci can be present. Occasionally enchondroma can grow in the form of sparsely separated small cartilage nodules. Calcifications, ossifications, or both are responsible for foci of ivory-white, and they may accentuate the overall lobular architecture of the lesion when they are concentrated on the periphery of cartilage islands.
Enchondromas are composed of mature cartilage that has lobular architecture (Figs. 6-11 and 6-12).7,10,26 The individual lobules can be separated by normal bone marrow spaces with hematopoietic elements (Fig. 6-12). More frequently, the individual lobules are incompletely separated by thin fibrovascular septa.7,10,29,30 Individual lobules of cartilage are often partially encased by mature lamellar bone. This feature is well preserved in incidentally resected enchondromas (see Figs. 6-11 and 6-12), but can also be observed in curettage specimens (Fig. 6-13). Lobules of cartilage, especially at the periphery of the lesion, can be sparsely separated and may appear as satellite nodules. In rare instances, lobules of cartilage can grow around the lamellar medullary bone (Fig. 6-12). Such a growth pattern should not be confused with the aggressive infiltration of the medullary cavity frequently seen in chondrosarcoma. The overall cellularity is very low, and in general, enchondromas appear very bland and have relatively few chondrocytes more or less evenly distributed within the hyaline cartilage matrix (see Figs. 6-14 and 6-15). More frequently, the cells form loosely arranged clusters, at least focally (Fig. 6-16). The individual chondrocytes are small, lie in lacunar spaces, and have small, dark nuclei (see Figs. 6-14 and 6-16). In general, the chondrocytes of enchondromas are similar to those seen in normal hyaline cartilage. Occasional binucleated cells and cells with so-called open nuclear chromatin can be present. The presence of more than one chondrocyte in a lacuna should not be considered an ominous finding and is not equated with binucleation or multinucleation of cartilage cells. The chondroid matrix is typically of hyaline type. Foci of fine or coarse calcifications and even of enchondral ossification can be present. Prominent myxoid change should not be present in enchondroma. If present, even when the cellularity is low, it usually suggests malignancy. One exception to this is in the small bones of the hands and feet, which may show prominent foci of myxoid change. In addition, enchondromas of the acral skeleton may show focal areas of hypercellularity with open chromatin architecture (Fig. 6-17). Such features would be considered a sign of malignancy in cartilage lesions of the major tubular bones but are within the spectrum of changes observed in enchondromas of the acral skeleton when combined with nonaggressive radiographic features. However, even at these skeletal sites, the change should be focal and the overall matrix should be hyaline. The lesion is usually clearly demarcated from the surrounding bone, and the periphery of cartilage lobules often shows encasement by a rim of lamellar bone (Fig. 6-13). In addition, especially in the short tubular bones, mild focal scalloping of the inner cortical surface can be present.
Special techniques are of little or no help in the diagnosis of enchondroma. Ultrastructurally, the cartilage cells have irregular cell surfaces and centrally located nuclei with condensed chromatin and a convoluted nuclear envelope (Fig. 6-18).
Similar to other cartilage lesions, in enchondroma, a thickening of the inner nuclear membrane is present. Immunohistochemically, the cells of enchondroma are positive for S-100 protein and vimentin. Enchondromas express cartilage lineage differentiation markers and invariably show nuclear positivity for SOX9 protein. SOX9 protein is also positive on all other tumors, benign or malignant, that express cartilage lineage differentiation. The cartilaginous nature of enchondroma is clearly evident on conventional hematoxylin-eosin sections, and special techniques are practically never required to support the diagnosis. Special techniques are also of no help in differentiating an enchondroma from a low-grade chondrosarcoma.
Image analysis and DNA flow cytometry show a diploid DNA histogram pattern with low proliferation rate.1,3,13,15 Cytogenetic studies detect diploid or near-diploid chromosomal complement with structural aberrations and translocations most often involving chromosomes 6, 12, and 24.12,28 Occasionally enchondromas may exhibit complex translocations involving several chromosomes such as 12, 15, and 21.12,24,28 Interestingly, chromosomal aberrations involving 6q13-21 have been associated with locally aggressive behavior of several benign cartilage lesions, including enchondroma.25 Recent identification of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) gene mutations mapping to the long arms of chromosomes 2 and 15, respectively, in solitary enchondromas, chondrosarcomas, and multiple enchondromas of Ollier’s disease and Maffucci’s syndrome provide interesting clues concerning the biology of cartilage neoplasia. Approximately 40% of solitary enchondromas show mutations of IDH1 or IDH2, whereas nearly 80% of multiple enchondromas and hemangiomas associated with Ollier’s disease and Maffucci’s syndrome show mutations of those genes, suggesting an important and possible driver role of these mutations in the development of cartilage neoplasia. Surprisingly, the same genes are frequently mutated in gliomas of the central nervous system and acute myeloid leukemia and less frequently in some other solid tumors. More detailed descriptions of the role of the IDH1 and IDH2 genes in the biology of cartilage neoplasia is provided in the section on enchondromatosis below.
Enchondromas must be distinguished from low-grade chondrosarcomas, particularly when they involve the metaphyses of long bones in middle-aged to elderly patients. The distinction can usually be made on the basis of absence of pain, no disturbance of the architecture of the surrounding cancellous bone or adjacent cortex, and a lack of cytologic atypia.7,10,11,29,30 The nuclei of cartilage cells in an enchondroma are small and uniform, and a homogeneous chromatin pattern is present.9,19 Multinucleated chondrocytes are infrequent, and the chondroid matrix is well formed, without prominent myxoid features.9,19
Chondroid differentiation in fibrous dysplasia can be distinguished from large solitary enchondromas on radiographs by the more diaphyseal localization and ground-glass appearance of the fibroosseous areas. The presence of fibroosseous elements in the sections adjacent to cartilaginous nodules is diagnostic for fibrocartilaginous dysplasia.
Enchondroma in Different Anatomic Sites
Enchondromas have a very characteristic anatomic distribution that differs significantly from that of chondrosarcoma. For that reason, the specific anatomic location of the lesion and its radiographic features are important and often decisive elements of the differential diagnosis.7,10,29,30 Therefore we provide separate descriptions of enchondroma with some principles of differential diagnosis in various anatomic sites.
Enchondroma of the Small Bones of the Hands and Feet.
As previously stated, the small bones of the hands and the feet are the most frequent anatomic sites for enchondroma, with approximately 60% of all cases located in these sites.2,7,10,11,29,27,30 The hands are more frequently involved than are the feet.
Enchondromas of the short tubular bones are typically diaphyseal lesions that sometimes involve the bone ends.14,21 They regularly produce endosteal scalloping and expand the bone contour (see Figs. 6-6 and 6-7). In the bones of the acral skeleton, these radiographic findings are not considered to be indicative of malignancy. Moreover, enchondromas in these sites are typically more cellular than enchondromas of other parts of the skeleton, and they may exhibit some nuclear atypia. The cartilage matrix is typically hyaline, but foci of myxoid change can be present in acral enchondromas. Regardless of the site, lesions that are exclusively myxoid, even if they have low cellularity, are suspicious for malignancy. In general, in the small bones of the hands and feet, a cartilage lesion can show features of endosteal scalloping, bone expansion, and increased cellularity and still behave as a benign enchondroma.2,7,10,15 If the same features are present in other anatomic sites, such as long tubular and flat bones, they should be considered suggestive of a low-grade malignant cartilage lesion. Typically small bone enchondromas are made clinically manifest by pain related to small infractions of the thinned cortex or complete pathologic fracture with displacement (see Fig. 6-6).
Enchondroma of Long Tubular Bones.
Enchondromas of the long tubular bones account for approximately 45% of cases.7,26,30 The femur and humerus are the most frequently involved long bones. The proximal metaphysis and shaft of the humerus and distal metaphysis of the femur are the most frequently involved sites (see Figs. 6-2 to 6-5). Enchondromas located in the midshaft are rare. Enchondromas are also considerably less common in the fibula and bones of the forearm.
Enchondromas of the long tubular bones present differential diagnostic problems with low-grade chondrosarcomas, which also occur in this part of the skeleton with comparable frequency. They may be microscopically indistinguishable from low-grade chondrosarcomas. The following are benign features of a solitary intramedullary cartilage lesion of the long bones. Such lesions are typically asymptomatic and are incidentally discovered on radiographic images or isotope scans performed for other reasons. They are small and usually measure less than 3 cm. The adjacent bone and the overlying cortex are normal. Microscopically, the cellularity is low, the chondrocytes have small dark nuclei, the matrix is hyaline, and the lesion is well demarcated (i.e., the islands of cartilage are bordered by bone trabeculae and there is no evidence of invasion of the haversian canals of the cortex). Any deviation from this pattern should be considered suspicious for malignancy.