Secondary Chondrosarcoma

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Patrick P. Lin, MD, et al undergo malignant transformation. Plain radiography may not demonstrate the cartilage cap as well as either CT or MRI do, which may lead the unwary clinician to underestimate the true size of the cap. Osteochondromas may have the appearance of an enlarged cartilage cap on T2-weighted magnetic resonance images when there is a large bursa around the cap. The fluid within the bursa appears similar to that of cartilage tissue because both entities have high water content. Gadolinium contrast is used to distinguish bursal structures from true cartilage tissue. The bursas have only rim enhancement of the bursal tissue without contrast enhancement of the fluid inside the bursa. Many clinicians believe that a cartilage cap with a thickness of 2 cm seems to be strong evidence for the presence of secondary chondrosarcoma. Some authors have stressed the importance of the character of the cartilage cap in addition to its absolute size. Ahmed et al 4 stated that “a qualitative assessment of the cartilaginous cap was more helpful than a precise measurement of cap thickness.” Irregularity of the surface of the cartilage cap correlated with the fuzzy appearance of the lesions on radiographs; this irregularity may reflect an increased invasive nature of the lesion. Pathology The diagnosis of secondary chondrosarcoma is confirmed by histologic examination of biopsy samples. Like conventional chondrosarcoma, secondary chondrosarcoma is not always easy to diagnose, and the histologic features alone may not be sufficient to determine that a lesion has become malignant. Most secondary chondrosarcomas are low grade. The overlap in appearance between benign lesions and low-grade cartilage tumors has led to a high rate of inter- and intraobserver variability in diagnosis. 24 Critical information from the clinical history and imaging studies must be correlated with the pathologic data to render the correct diagnosis. On the pathology slides, sarcomatous transformation is usually identified by the presence of malignant chondroid tissue. Hallmarks include hypercellularity, binucleate cells, multiple cells in lacunae, atypical nuclei, and myxoid changes in the hyaline cartilage matrix (Figure 2). Thickening of the cartilage cap can be observed grossly. 23 A few abnormal features may make it difficult to distinguish the cartilage of osteochondromas from low-grade chondrosarcomas on the basis of histologic findings alone, even for experienced pathologists. 25,26 There may be mild nuclear atypia, slight hypercellularity, and occasional binucleate cells. In these cases, the radiographic and clinical findings are important. 27 A lesion with a thin cartilage cap that has not grown or changed for years is unlikely to have transformed into a malignant tumor. Conversely, sudden growth in a cap with marked enlargement of the cap strongly suggests the presence of chondrosarcoma, even when the histologic findings show minimal abnormalities that would be compatible only with a diagnosis of grade 1 chondrosarcoma (low grade). An important feature consistent with malignancy is permeative infiltration of soft tissues and the presence of discrete nodules of cartilage in the soft tissues separated from the main tumor mass. In one study, 57% of all cases of secondary chondrosarcoma showed histologic evidence of such permeative changes on the pathology slides. 4 Medullary extension of cartilaginous tumor into bone also demonstrates invasive and malignant behavior. This may be found in up to one third of cases, and it tends to be more common in broad-based osteochondromas. 13 The grading of secondary chondrosarcomas is similar to that of primary chondrosarcomas and includes grade 1, low; grade 2, intermediate; and grade 3, high. 14,28 In general, increasing grade is associated with greater cellularity, number of binucleate cells, and mitoses. Most secondary chondrosarcomas are grade 1 or 2 lesions. In the pub- October 2010, Vol 18, No 10 611
<strong>Secondary</strong> <strong>Chondrosarcoma</strong> lished data of the large series that we reviewed, more than three fourths of the cases were grade 1 tumors, and nearly all of the remaining lesions were grade 2. 4,5,7,11,13 Only 1% of cases were reported to be grade 3. Figure 2 Genetics and Mutations Histologic comparison of osteochondroma and secondary chondrosarcoma. A, Cartilaginous tissue of an osteochondroma demonstrating features that recapitulate the hyaline cartilage of articular surfaces. Note the gradual enlargement of cells as they near the subchondral bone and become hypertrophic. Most cells reside in solitary lacunae, with occasional lacunae having two cells (arrowhead). The cells are relatively sparse in the abundant extracellular matrix (hematoxylin-eosin, original magnification ×40). B, Grade 2 secondary chondrosarcoma demonstrating greater cellularity and less discernible organization of the chondrocytes. Lacunae with multiple cells are more common. Because cells retract from the walls of the lacunae during the fixation process, pleomorphism of cells is not easy to identify (hematoxylineosin, original magnification ×20). C, Osteochondroma under high-power magnification demonstrating cells that are fairly well-spaced in their lacunae. Slight atypia may be visible, making the distinction between benign lesions and low-grade chondrosarcoma difficult on the basis of histology alone. Certain lacunae contain two cells (hematoxylin-eosin, original magnification ×400). D, Grade 1 secondary chondrosarcoma under high-power magnification demonstrating atypical features, such as the binucleate cell in the center of the field. No significant nuclear pleomorphism is present (hematoxylin-eosin, original magnification ×400). Hereditary multiple exostosis (HME), also referred to as multiple hereditary exostosis and hereditary multiple osteochondromatosis, is a rare familial disease characterized by multiple osteochondromas throughout the skeleton. The disease is inherited as an autosomal dominant condition with high penetrance. Three related genes have been implicated in the disorder, EXT1, EXT2, and EXT3, which are located on 8q24, 11p13, and 19p, respectively. 29-31 EXT1 and EXT2 mutations are more common and make up most cases. 32 Patients with EXT1 mutation tend to have more severe phenotypes than do patients with EXT2 mutation. 32 It is not clear how the EXT genes are related to the pathophysiology of osteochondromas. Mutation of the genes usually results in truncated forms of the proteins, which are needed for the synthesis of heparan sulfate. This may secondarily impair diffusion of cellsignaling molecules. 33 A genetic model for cartilaginous tumorigenesis in the setting of HME has been proposed. 34 First, inactivation of both copies of the EXT1 gene in cartilage cells is essential for the formation of osteochondroma. This typically occurs via loss of heterozygosity in sporadic cells. Cells that maintain one normal copy of the gene are apparently normal. Of note, it appears that solitary osteochondromas also develop as a result of mutation of both copies of an EXT gene, the difference being that this occurs in isolated cells and no germline mutation is inherited. Without further mutations in other genes, the lesion remains benign; most osteochondromas remain in this state and do not progress further. One or more additional mutations in other genes 612 Journal of the American Academy of Orthopaedic Surgeons
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Secondary Chondrosarcoma

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