ChondrosarcomaPractice EssentialsChondrosarcoma is a collective term for a group of tumors that consist predominantly of cartilage and that range from low-grade tumors with low metastatic potential to high-grade, aggressive tumors characterized by early metastasis.Essential update: Stereotactic radiosurgery demonstrates superiority over conventional radiotherapy for sarcoma that has metastasized to the spineIn a study of 88 patients with high-grade sarcoma that had spread to the spine, Folkert and colleagues found that treatment with image-guided stereotactic radiosurgery (IG-SRS) provided 87.9% local control at 12 months. By comparison, 12-month local control rates with conventional radiotherapy have historically ranged from 50-77%. In the study, 12-month local control was better with single-fraction IG-SRS than with hypofractionated IG-SRS (90.8% vs 84.1%;P= .007). IG-SRS treatment was well tolerated.[1, 2]Chondrosarcoma types and gradesDifferent types of chondrosarcoma have been described, as follows: Conventional chondrosarcoma, which accounts for nearly 90% of all chondrosarcomas Dedifferentiated chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma Juxtacortical chondrosarcoma Secondary chondrosarcomaBenign cartilage lesions can be difficult to differentiate from slow-growing, low-grade chondrosarcomas. Secondary chondrosarcoma can occur in a previously benign cartilaginous lesion.Chondrosarcomas can be classified into the following 3 histologic grades, depending on findings of cellularity, atypia, and pleomorphism: Grade I (low grade) Cytologically similar to enchondroma[3]; cellularity is higher, with occasional plump nuclei with open chromatin structure Grade II (intermediate grade) Characterized by a definite and increased cellularity; distinct nucleoli are present in most cells, and foci of myxoid change may be seen Grade III (high grade) Characterized by high cellularity, prominent nuclear atypia, and the presence of mitosisThe higher the grade, the more likely the tumor is to spread and metastasize. Grade I lesions rarely metastasize, whereas 10-15% of grade II lesions and more than 50% grade III lesions metastasize.Clinical PresentationClinical features of chondrosarcomas are as follows: Deep, dull, achy pain Pain at night Nerve dysfunction of the lumbosacral plexus or the sciatic or femoral nerves, with pelvic lesions near a neurovascular bundle Limitation of joint range of motion and disturbance of joint function, with chondrosarcomas close to a joint Pathologic fractureDiagnosisThe workup rests primarily on diagnostic imaging modalities (eg, plain radiography, as well as CT and MRI).Plain radiography Chondrosarcomas are usually large (> 5 cm) The bony contour appears thinned and expanded, and multiple surface erosions (endosteal scalloping) are seen Cortical thickening may also be visible The extent of bony destruction depends on the histologic grade of the tumor The periosteum overlying the tumor may be elevated; this leads to new bone formation that results in hazy cortical irregularity and fuzziness or parallel periosteal new bone formation Variable amounts of stippled or punctuate calcification are seen In some cases, calcifications resemble popcorn or commas; in others, arcs and rings of calcification are seen around lobules of cartilage The typical appearance of a dedifferentiated chondrosarcoma is an area of punctate opacities surrounded by a permeating, destructive lytic lesionSecondary malignant degeneration should be suspected when sequential follow-up radiographs of benign cartilage tumors show the following findings: Growth of the lesion Decreased calcification and increased lysis Endosteal erosion Permeative lesions with destruction of the cortex Soft-tissue mass Growth in a previously stable exostosis or enchondroma in an adult Expansion of the cartilaginous cap in exostosisMRI The investigation of choice for assessing the extent of a chondrosarcoma Helps delineate the extent of soft-tissue involvement Important for preoperative planning and for confirming or diagnosing recurrence at a surgically treated siteCT scanning May be useful for detecting subtle calcifications in the matrix when the diagnosis is in doubt May improve visualization of bony destruction and depict the extent of bony delineationBiopsyPerforming a truly representative biopsy of a chondrosarcoma is challenging because the lesion is composed of areas that carry different histologic grades. Identification of the most aggressive component of the tumor is critical. Considerations when performing biopsy are as follows: Biopsy should be directed at areas that may harbor foci of high-grade tumor, such as areas of endosteal scalloping, soft-tissue components, or diffusely enhancing areas with minimal mineralization Biopsy can be performed with either an open or a closed technique[4] Closed biopsy involves fine-needle aspiration (FNA) cytology or core biopsy Discussion with the radiologist and the histopathologist is essential in obtaining the correct tissue for biopsy With cartilaginous tumors, histopathologic examination of the biopsy specimen alone does not permit accurate classification of the tumor Biopsy should be done as meticulously as possible, to avoid seeding of the biopsy tract with bone-tumor cells When a definitive procedure is performed, the whole tract should be completely excisedStagingThe Enneking staging system for musculoskeletal sarcomas is applicable to chondrosarcomas, as follows[5]: Stage I (low-grade tumor): I-A, intracompartmental; I-B, extracompartmental Stage II (high-grade tumor): II-A, intracompartmental; II-B, extracompartmental Stage III (distant metastasis)ManagementSurgery is the primary treatment for any chondrosarcoma. Complete, wide surgical excision of the chondrosarcoma is the preferred method when it is feasible. Radiotherapy and chemotherapy play limited roles in primary treatment. An exception is their use as adjuvant therapy or palliative treatment for tumors in surgically inaccessible areas or diffuse metastasis.Image libraryPlain radiograph shows a low-grade chondrosarcoma in the pelvis(B). An incidental finding is that the proximal femur contains a benign enchondroma(A).OverviewChondrosarcoma is a tumor of mesenchymal origin that predominantly is made of cartilage; it is the second most common primary malignant tumor of the bone. Chondrosarcoma is a collective term that encompasses a group of heterogeneous lesions with diverse morphologic features and clinical behaviors.[6]These lesions range from low-grade tumors with low metastatic potential to high-grade, aggressive tumors characterized by early metastasis.The term chondrosarcoma should be used for a malignant tumor of the cartilage when the tumoral matrix is entirely cartilage. If the tumor exhibits bone-forming elements and primitive mesenchymal elements in addition to cartilaginous differentiation, it should not be classified as a chondrosarcoma, because its clinical behavior and therapeutic responses differ from those of a primary malignant chondrosarcoma.Tumors with the aforementioned elements (ie, the presence of bone-forming elements and primitive mesenchymal elements in addition to cartilaginous differentiation) usually behave like chondroblastic osteosarcomas and are more aggressive than the conventional chondrosarcomas.Different types of chondrosarcoma have been described, as follows: Conventional chondrosarcoma, which accounts for nearly 90% of all chondrosarcomas Dedifferentiated chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma Juxtacortical chondrosarcoma Secondary chondrosarcomaDespite various investigations, it may be difficult to differentiate a benign cartilage lesion from a slow-growing, low-grade chondrosarcoma. Secondary chondrosarcoma can occur in a previously benign cartilaginous lesion.PathophysiologyChondrosarcomas may be divided into primary and secondary lesions on the basis of their origins.[7]Primary chondrosarcomas arise de novo, whereas secondary chondrosarcomas arise from preexisting lesions of the cartilage.Except for their origin in preexisting cartilaginous conditions, secondary chondrosarcomas are similar to conventional chondrosarcomas in all respects. In addition, the genes responsible for the lesions depend on the primary benign cartilaginous condition. Secondary chondrosarcomas occur in individuals with Ollier disease, Maffucci syndrome, multiple hereditary exostosis (diaphyseal aclasis), solitary osteochondroma, solitary enchondroma, solitary periosteal enchondroma, Paget disease, or radiation injury.GeneticsBovee et al reported that most peripheral chondrosarcomas had a higher proliferation rate on Ki-67 immunohistochemistry and that they were associated with loss of heterozygosity at many loci.[8, 9]Only a few chondrosarcomas had anomalies, which were restricted to 9p21, 10, 13q14, and 17p13. These anomalies were peridiploid or near-haploid. Structural chromosomal aberrations and genetic instability were seen during cytogenetic analysis of well-differentiated, grade I chondrosarcomas. Nearly all grade III and some grade II chondrosarcomas were aneuploid.Amplification of thec-mycproto-oncogene[10]andfos/jun[11]has also been implicated in the pathogenesis of chondrosarcoma.With extraskeletal myxoid chondrosarcomas,[12]the t(9;22)(q22;q12) translocation is common, though t(9;17)(q22;q11.2) has also been described. Numerous genetic alterations have been found for dedifferentiated chondrosarcomas, but a shared loss of chromosome 13 suggests that the differentiated and dedifferentiated components originate from a common precursor.Histologic gradingChondrosarcomas can be classified into the following 3 histologic grades, depending on findings of cellularity, atypia, and pleomorphism: Grade I (low grade) This is cytologically similar to enchondroma[3]; cellularity is higher, with occasional plump nuclei with open chromatin structure Grade II (intermediate grade) This is characterized by a definite and increased cellularity; distinct nucleoli are present in most cells, and foci of myxoid change may be seen Grade III (high grade) This is characterized by high cellularity, prominent nuclear atypia, and the presence of mitosisThe higher the grade, the more likely the tumor is to spread and metastasize. Grade I lesions rarely metastasize, whereas 10-15% of grade II lesions and more than 50% grade III lesions metastasize.Low-grade chondrosarcomas resemble benign cartilaginous tumors, and it is difficult to differentiate the 2 lesions on the basis of histologic features alone. The essential differences are the limited growth potential of benign cartilaginous tumors and the slow growth capacity of low-grade chondrosarcomas.Dedifferentiated chondrosarcomas are more aggressive than grade III conventional chondrosarcomas.EpidemiologyFrequency by tumor typeConventional central chondrosarcomas account for nearly 80-90% of all chondrosarcomas and 20-27% of all primary bone sarcomas[13].They demonstrate a predilection for the axial skeleton. Rates of involvement are as follows: pelvis and ribs, 45%; ilium, 20%; femur, 15%; humerus, 10%; and others, 10%. The spine and the craniofacial bones are rarely involved.Dedifferentiated chondrosarcomas are responsible for as many as 10% of all chondrosarcomas. The femur is the site most commonly involved, accounting for one-third of all dedifferentiated chondrosarcomas. The other sites of involvement are the pelvis (20%), the humerus (16%), the ribs (7%), and the scapula (7%).Clear cell chondrosarcomas account for fewer than 5% of all chondrosarcomas. They have a predilection for the ends of long tubular bones, involving the epiphysis. Like chondroblastomas, these lesions extend to involve the articular cartilage. The proximal aspect of the femur is the site most often affected (45%), followed by the proximal portion of the humerus.Fewer than 2% of all chondrosarcomas are mesenchymal chondrosarcomas. The maxilla and the mandible are the most common sites of involvement, followed by the vertebrae, the ribs, the pelvis, and the humerus. The appendicular skeleton is rarely involved.Juxtacortical chondrosarcomas are rare and generally involve the surface of the diaphysis or metaphysis of long tubular bones.Age-, sex-, and race-related demographicsIncidences do not differ among ethnic groups. Sex and age distributions are listed in the table below.Table 1. Sex Ratios and Ages of Peak Incidence for Different Types of Chondrosarcoma(Open Table in a new window)ChondrosarcomaMale-to-Female RatioAge of Peak Incidence

ConventionalAlmost 1:1 (slight male predominance)50-70 y (most common > 50 y, gradual increase with age)

DedifferentiatedSimilar to the ratio above> 50 y

Clear cell2.4:120-40 y (common 10-90 y)

Mesenchymal1:120-30 y (common in teenagers and young adults)

Juxtacortical1:120-40 y

Clinical PresentationDeep, dull, achy pain is a common symptom in chondrosarcomas. Pain at night is another feature. Although the finding of pain is important for distinguishing malignant lesions from benign cartilaginous lesions, it can be somewhat unreliable when the small bones of the hands and feet are involved.If the lesion is near a neurovascular bundle, as pelvic lesions are, the patient may present with nerve dysfunction of the lumbosacral plexus or the sciatic or femoral nerves. If a chondrosarcoma is close to a joint, it may limit the joints range of motion and disturb its function. These signs are common with juxtacortical chondrosarcomas, though they can also be present with pathologic fractures. More than half of all patients with dedifferentiated chondrosarcomas present with a pathologic fracture.The mean interval from pain to diagnosis is 19.4 months for grade I and grade II chondrosarcomas and 15.5 months for grade III chondrosarcomas, as per the Rizzoli institute experience.[14]Clear cell chondrosarcomas and mesenchymal chondrosarcomas can produce symptoms for longer than 1 year because of their low-grade nature. Mesenchymal chondrosarcomas can manifest as a soft-tissue mass.Differential DiagnosisThe differential diagnosis includes the following conditions: Chondroblastoma Chondroma Chondromyxoid fibroma Chordoma Fibrosarcoma Fibrous dysplasia Fibrous histiocytoma Metastatic carcinoma Osteosarcoma Paget sarcoma[15, 16] Synovial chondromatosisLaboratory TestsRoutine blood investigations are performed as part of preoperative examinations. Tests of liver, lung, and renal functionwith bone biochemical analysesmay be used for preoperative assessment and for evaluations of the distant spread of tumors (metastasis).Otherwise, workup rests primarily on diagnostic imaging modalities (eg, plain radiography, as well as computed tomography [CT] and magnetic resonance imaging [MRI]).Plain RadiographyThe typical appearance of a cartilaginous lesion on plain radiographs is discrete calcification (see the image below). The lesion may be radiolucent on radiographs, which may show stippled or punctate calcifications. Appearances vary from lesion to lesion, depending on the amount of mineralization that has occurred.Plain radiograph shows a low-grade chondrosarcoma in the pelvis(B). An incidental finding is that the proximal femur contains a benign enchondroma(A).Characteristic findingsChondrosarcomas are usually large (> 5 cm). The bony contour appears thinned and expanded, and multiple surface erosions (endosteal scalloping) are seen. Chondrosarcomas sometimes produce cortical thickening as well. The extent of bony destruction depends on the histologic grade of the tumor.The periosteum overlying the tumor may be elevated. This effect leads to new bone formation that results in hazy cortical irregularity and fuzziness or parallel periosteal new bone formation. This process differentiates chondrosarcomas from osteosarcomas, which results in perpendicular periosteal new bone formation that has a sunburst appearance.Variable amounts of stippled or punctuate calcification are seen. In some cases, calcifications resemble popcorn or commas; in others, arcs and rings of calcification are seen around lobules of cartilage. The typical appearance of an dedifferentiated chondrosarcoma is an area of punctate opacities surrounded by a permeating, destructive lytic lesion.Endosteal scalloping and thinning may be observed with most lesions. Sometimes, as in clear cell chondrosarcoma, images depict cortical thickening around the lysis with endosteal expansion. High-grade lesions produce permeative lesions as they destroy the cortex.Findings suggestive of secondary malignant degenerationSecondary malignant degeneration should be suspected when sequential follow-up radiographs of benign cartilage tumors show the following findings: Growth of the lesion Decreased calcification and increased lysis Endosteal erosion Permeative lesions with destruction of the cortex Soft-tissue mass Growth in a previously stable exostosis or enchondroma in an adult Expansion of the cartilaginous cap in exostosisMRIMRI is the investigation of choice for assessing the extent of a chondrosarcoma; it also helps delineate the extent of soft-tissue involvement (see the images below). Its ability to determine the exact extent of the tumor and the degree to which various soft-tissue compartments are involved make it an important tool for preoperative planning. In addition, MRI is an important study for confirming or diagnosing recurrence at a surgically treated site.T1-weighted MRI shows a low-signal-intensity lesion in the pelvis, a chondrosarcoma.T2-weighted MRI shows a high-signal-intensity lesion in the pubis, a chondrosarcoma.MRI of a chondrosarcoma shows contrast enhancement of the lesion. A-Enchondroma; B-ChondrosarcomaCT, Bone Scan, and UltrasonographyCT may be useful for detecting subtle calcifications in the matrix so as to help diagnose cartilaginous tumors when the findings are in doubt. CT may improve visualization of bony destruction and depict the extent of bony delineation.Bone scanning and chest CT are used for systemic staging of the tumor before surgical treatment. Abdominal CT, abdominal ultrasonography, or both may be used for this purpose as well.BiopsyPerforming a truly representative biopsy of a chondrosarcoma is challenging because the lesion is composed of areas that carry different histologic grades. A tumor should be graded on the basis of its most aggressive component. Hence, the challenge during biopsy is to ensure that the most aggressive part is identified.Biopsy should be directed at areas that may harbor foci of high-grade tumor, such as areas of endosteal scalloping, soft-tissue components, or diffusely enhancing areas with minimal mineralization. The rationale behind targeting areas with minimal calcification of the matrix is that high-grade areas usually contain myxomatous matrix that is relatively resistant to calcification. By comparison, low-grade areas usually contain chondroid matrix that calcifies.Biopsy can be performed with either an open or a closed technique.[4]Closed biopsy involves fine-needle aspiration (FNA) cytology or core biopsy. Core biopsy through a Tru-Cut biopsy or a core-needle biopsy yields results equivalent to those of open biopsy. Discussion with the radiologist and the histopathologist is essential in obtaining the correct tissue for biopsy. However, with cartilaginous tumors, histopathologic examination of the biopsy specimen alone does not permit accurate classification of the tumor.Chondrosarcomas are mostly gelatinous. Therefore, the risk of seeding of the biopsy tract with bone-tumor cells is high. Furthermore, because the cartilaginous tumor matrix is avascular, malignant cartilage cells can survive when they are spilled into a wound. For these reasons, biopsy of a chondrosarcoma should be done as meticulously as possible. When a definitive procedure is performed, the whole tract should be completely excised.In summary, biopsy of a chondrosarcoma is not a benign procedure and must therefore be planned efficiently. The normal principles of biopsy for any tumor should be adhered to, as follows: The biopsy should be done by the surgeon who will be providing definitive treatment; if that is not feasible, it should least be done after a detailed discussion with the surgeon The path selected for the biopsy should be in the same line as that to be used for the definitive operation, so that the biopsy tract will be excised in the course of surgical treatment The biopsy tract should follow a straight line and avoid contamination of joints, uninvolved structures, neurovascular bundles, and bones; preoperative planning is essential, and the biopsy tract should not be placed in the flap that will be used for coverage after excision of the tumor Transverse incisions should be avoided Appropriate handling of tissue after the biopsy specimen is obtained is essential; this should be decided before the operation in consultation with the histopathologist Adequate hemostasis should be achieved before closure A suture may be used to mark the skin entry site to facilitate excision of the biopsy tract during definitive surgeryHistologic FindingsGross findingsThe cartilaginous nature of chondrosarcomas is apparent on cross-section. The lesion has a grossly lobulated architecture with translucent, gray-black hyaline tissue. Intense mineralization accentuates lobules at the periphery. The myxoid variety may be gelatinous. Two featurestumoral oozing from the cut surface and frank liquefactionhelp in differentiating malignant tumors from benign tumors of cartilage. Chondrosarcomas appear as sessile, lobulated masses in the pelvis and have large extraosseous components.Microscopic findingsA tumor must be uniformly cartilaginous to be classified as a chondrosarcoma. Chondrosarcomas contain chondroid matrix with increased cellularity, and they have binucleate cells. As noted (see Pathophysiology), these tumors are classified into low, intermediate, and high grades (grades I, II, and III, respectively).Low-grade chondrosarcomas typically look like enchondromas. Intermediate-grade tumors contain cartilage cells that have enlarged round nuclei with prominent nucleoli. Their cytoplasm shows prominent rough cytoplasmic reticula, mitochondria, and large amounts of glycogen. High-grade tumors are characterized by high cellularity, prominent nuclear atypia, and mitosis. High-grade tumors constitute 5-10% of all chondrosarcomas.Immunohistochemical tests show the presence of S-100 protein and vimentin in low- and intermediate-grade chondrosarcomas. However, results for S-100 protein and vimentin are focally negative in high-grade lesions, especially among dedifferentiated areas. Immunohistochemical staining is not routinely indicated for the diagnosis of cartilaginous tumors. These lesions are more readily diagnosed with conventional hematoxylin-eosin stains than with immunohistochemical stains.Measurements of DNA ploidy reveal that low-grade tumors are diploid, whereas intermediate- and high-grade tumors are aneuploid. Aneuploidy is correlated with the aggressiveness of the chondrosarcoma.Chromosomal anomalies reveal an accumulation of p53 protein; in high-grade lesions, this finding indicates a poor prognosis.StagingThe Enneking staging system for musculoskeletal sarcomas is applicable to chondrosarcomas, as follows[5]: Stage I (low-grade tumor) - I-A, intracompartmental; I-B, extracompartmental Stage II (high-grade tumor) - II-A, intracompartmental; II-B, extracompartmental Stage III (distant metastasis)Treatment & ManagementRadiotherapy and chemotherapyRadiotherapy and chemotherapy play limited roles in primary treatment. An exception is their use as adjuvant therapy or palliative treatment in surgically inaccessible areas.Diffuse metastasis is usually an indication for systemic radiotherapy or chemotherapy. The results are generally poor, as they are in dedifferentiated chondrosarcoma, for which the 1-year survival rate is 10%.[13]Chemotherapy and radiotherapy may be used in dedifferentiated chondrosarcoma because distant systemic metastasis may be present at the time of diagnosis. However, current evidence indicates that surgery with clear margins remain the primary treatment for dedifferentiated chondrosarcomas a well. Grimer et al recommended further use of chemotherapy in such cases only as a trial or treatment protocol.[17]Surgical therapySurgery is the primary treatment for any chondrosarcoma. Complete, wide surgical excision of the chondrosarcoma is the preferred method when it is feasible. Success depends on the stage of the disease, with low-grade intracompartmental lesions offering the best prognosis after complete surgical resection with surgically clear margins. Lesions with isolated pulmonary metastasis can still be surgically resected if metastasectomy of the isolated pulmonary lesion is feasible.Chondrosarcomas in the appendicular skeleton are amenable to wide excision. Hence, these lesions tend to fare better with surgery than those occurring in the axial skeleton. Complete removal of most lesions in the axial skeleton is difficult. Complete en-bloc excision can cure clear cell chondrosarcomas. Surgery remains the primary treatment for mesenchymal chondrosarcomas as well.Follow-upRegular follow-up is required to rule out local recurrences of chondrosarcoma and distant metastases. Regular follow-up clinical evaluations and radiologic investigations are required.Outcome and PrognosisThe prognosis is correlated with the grade and stage of the lesion at the time of diagnosis.[18]The location of the lesion is also important because tumors in areas where complete wide resection is possible are associated with better prognoses.Recurrence and distant metastasis may develop. The metastasis rate for primary chondrosarcoma is higher than that for secondary chondrosarcoma, and the rate of distant metastasis is higher in patients with local recurrence than in those without local recurrence.Mortality and morbidity data for the various types of chondrosarcomas are summarized below.Conventional chondrosarcomaEvans et al[19]showed that the survival rate depends on the histologic grade of the tumor, as follows: Grade I tumors - 90% survival at 5 years Grade II tumors - 81% survival at 5 years Grade III tumors - 29% survival at 5 yearsOverall, the 5-year survival rate for conventional chondrosarcomas is 48-60%.[13]Intralesional surgery is not advised even in grade I lesions, especially in the pelvis, because the local recurrence rate is 100% in such cases.Grade I tumors do not metastasize, whereas 66% of grade III tumors do. The most common sites for metastases are the lungs. Recurrences typically appear 5-10 years or longer after surgery.Dedifferentiated chondrosarcomaDedifferentiated chondrosarcoma is highly lethal. It is associated with a 10% survival rate after 1 year. Even with early surgical treatment, disseminated hematogenous metastasis occurs in most patients.[13]Clear cell chondrosarcomaAlthough clear cell chondrosarcomas are low-grade tumors, they can lead to distant metastasis. Late recurrences (>10 y) have been described. Overall, the recurrence rate is 16%[13].Mesenchymal chondrosarcomaThe 5-year survival rate for mesenchymal chondrosarcoma is less than 50%, with an overall 10-year survival rate of 28%.[13]Juxtacortical chondrosarcomaJuxtacortical chondrosarcomas are low- to intermediate-grade lesions; the prognosis for these tumors is better than that for other tumors.[13]