Chondrosarcoma

Chondrosarcoma is a tumor of mesenchymal origin that predominantly is made of cartilage; it is the second most common primary malignant tumor of bone. Chondrosarcoma is a collective term that encompasses a group of heterogeneous lesions with diverse morphologic features and clinical behaviors.[1, 5] 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 chondrosarcoma

Despite 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.

Guidelines for the management of chondrosarcoma have been published (see Guidelines).

Chondrosarcomas may be divided into primary and secondary lesions on the basis of their origins.[6] 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.

Genetics

Bovee 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.[7, 8] 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 the c-myc proto-oncogene[9] and fos/jun[10] has been implicated in the pathogenesis of chondrosarcoma.

With extraskeletal myxoid chondrosarcomas,[11] 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.

Isocitrate dehydrogenase 1 and 2 (IDH1, 2) mutations have been identified in chondrosarcomas.[12, 13]

Histologic grading

Chondrosarcomas can be classified into the following three histologic grades, depending on findings of cellularity, atypia, and pleomorphism:

• Grade I (low grade) – This is cytologically similar to enchondroma ^[2] ; 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 mitosis

The 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 two 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.

Frequency by tumor type

Conventional central chondrosarcomas account for nearly 80-90% of all chondrosarcomas and 20-27% of all primary bone sarcomas[14] .They demonstrate a predilection for the axial skeleton. Rates of involvement are as follows:

• Pelvis and ribs, 45%
• Ilium, 20%
• Femur, 15%
• Humerus, 10%
• 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 demographics

Incidences do not differ among ethnic groups. Sex and age distributions are listed in Table 1 below.

Table 1. Sex Ratios and Ages of Peak Incidence for Different Types of Chondrosarcoma (Open Table in a new window)

Chondrosarcomas are considerably rarer in children and adolescents than in adults.[15]

The prognosis is correlated with the grade and stage of the lesion at the time of diagnosis.[16] The location of the lesion is also important because tumors in areas where complete wide resection is possible are associated with better prognoses. In general, chondrosarcomas of the head and neck are associated with better disease-specific survival and overall survival rates than chondrosarcomas located elsewhere.[17]

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.

In children and adolescents, chondrosarcoma of bone has a very good prognosis and is less aggressive than in older patients.[15]

Mortality and morbidity data for the various types of chondrosarcomas are summarized below.

Conventional chondrosarcoma

Evans et al[18] 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 years

Overall, the 5-year survival rate for conventional chondrosarcomas is 48-60%.[14] 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 chondrosarcoma

Dedifferentiated 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.[14]

Clear cell chondrosarcoma

Although clear cell chondrosarcomas are low-grade tumors, they can lead to distant metastasis. Late recurrences (>10 years) have been described. Overall, the recurrence rate is 16%[14] .

Mesenchymal chondrosarcoma

The 5-year survival rate for mesenchymal chondrosarcoma is less than 50%, with an overall 10-year survival rate of 28%.[14]

Juxtacortical chondrosarcoma

Juxtacortical chondrosarcomas are low- to intermediate-grade lesions; the prognosis for these tumors is better than that for other tumors.[14]

Deep, 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 joint’s 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.[19]

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.

Routine blood investigations are performed as part of preoperative examinations. Tests of liver, lung, and renal function—with bone biochemical analyses—may 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]).

The typical appearance of a cartilaginous lesion on plain radiographs is discrete calcification. 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.

Characteristic findings

Chondrosarcomas 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. (See the image below.)

Plain radiograph shows low-grade chondrosarcoma in pelvis (B). Incidental finding is that proximal femur contains benign enchondroma (A).

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 degeneration

Secondary 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 exostosis

MRI 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. Dynamic contrast-enhanced MRI has been reported to be useful and complemetary to standard MRI for distinguishing benign from malignant lesions.[22]

T1-weighted MRI shows low-signal-intensity lesion in pelvis: chondrosarcoma.

T2-weighted MRI shows high-signal-intensity lesion in pubis: chondrosarcoma.

MRI of chondrosarcoma (B) shows contrast enhancement of lesion. Enchondroma (A) is also present.

CT 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. It has been suggested that positron emission tomography (PET)-CT can help in differentiating between chondromas and chondrosarcomas in the long bones.[23]

Bone scanning and chest CT are used for systemic staging of the tumor before surgical treatment. Abdominal CT, abdominal ultrasonography (US), or both may be used for this purpose as well.

Performing 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.[3] 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. Image-guided needle biopsy may be more reliable for grading chondrosarcoma in long bones than in the pelvis.[24]

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 surgery

Gross

The 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 features—tumoral oozing from the cut surface and frank liquefaction—help in differentiating malignant tumors from benign tumors of cartilage. Chondrosarcomas appear as sessile, lobulated masses in the pelvis and have large extraosseous components.

Microscopic

A 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 Overview, 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.

The Enneking staging system for musculoskeletal sarcomas is applicable to chondrosarcomas, as follows[4] :

• 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)

The National Comprehensive Cancer Network (NCCN) follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS) for staging.[25]  The European Society for Medical Oncology (ESMO), the European Reference Network for Paediatric Cancers (PaedCan), and the European Network for Rare Adult Solid Cancer (EURACAN) do not provide a specific recommendation for which system should be followed.[26]

Guidelines for treatment of chondrosarcoma have been developed by the National Comprehensive Cancer Network (NCCN)[25] ; jointly by the European Society for Medical Oncology (ESMO), the European Reference Network for Paediatric Cancers (PaedCan), and the European Network for Rare Adult Solid Cancer (EURACAN)[26] ; and by the Sarcoma European Latin-American Network (SELNET).[27]  (See Guidelines.) For further information, see Bone Sarcoma Guidelines. 

Radiotherapy 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%.[14]

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 as well. Grimer et al recommended further use of chemotherapy in such cases only as a trial or treatment protocol.[28]

Surgery 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.

A retrospective study by Park et al suggested that intralesional curettage with cryotherapy appears to be a safe and reasonable surgical option for patients with low-grade chondrosarcoma lesions confined to bone (Enneking stage I-A).[29]

Regular follow-up is required to rule out local recurrences of chondrosarcoma and distant metastases. Regular follow-up clinical evaluations and radiologic investigations are required.

NCCN recommendations for treatment of chondrosarcoma are as follows[25] :

• Enrollment in a clinical trial should be considered when available; in addition, whenever possible patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team
• Wide excision or intralesional excision with or without adjuvant therapy for resectable low-grade and intracompartmental lesions
• Wide excision is preferred for pelvic low-grade tumors
• High-grade (grade II, III), clear cell, or extracompartmental lesions, if resectable, should be treated with wide excision
• Wide excision should provide negative surgical margins and may be achieved by either limb-sparing surgery or amputation
• Postoperative treatment with proton and/or photon beam radiation for tumors in unfavorable location
• Consider radiation therapy for unresectable tumors

No established chemotherapy regimens exist for grade I-III tumors; treatment of patients with dedifferentiated chondrosarcoma should follow osteosarcoma guidelines; treatment of patients with mesenchymal tumor should follow Ewing sarcoma guidelines; dasatinib is an option. Standard sarcoma chemotherapy agents can be tried to palliate metastatic disease. 

NCCN recommendations for treatment of local recurrence of chondrosarcoma are as follows[25] :

• Wide excision if resectable
• Consider radiation therapy or re-resection to achieve negative surgical margins following wide excision with positive margins
• Radiation therapy for unresectable recurrences
• Surgical excision or participation in a clinical trial for patients with systemic recurrence of a high-grade chondrosarcoma

European Society for Medical Oncology, European Reference Network for Paediatric Cancers, and European Network for Rare Adult Solid Cancer (ESMO-PaedCan-EURACAN) guidelines recommend that low-grade central chondrosarcomas in the long bones of the limbs be managed by curettage, with or without adjuvant therapy (eg, phenol, cement, cryotherapy) and low-grade peripheral chondrosarcomas be surgically excised.[26] Higher-grade chondrosarcomas and all chondrosarcomas of the pelvis or axial skeleton should be surgically excised with wide margins. For dedifferentiated chondrosarcoma, if wide margins cannot be achieved with limb salvage, consideration of amputation is recommended.

The ESMO-PaedCan-EURACAN guidelines are generally in agreement with NCCN regarding chemotherapy regimens for mesenchymal chondrosarcoma and also note the following[26] :

• Dedifferentiated chondrosarcoma is often treated as a high-grade bone sarcoma, with systemic and local therapies that need to be adapted to the patient’s age
• Skull-base chondrosarcomas can be treated with high-dose radiation therapy, including proton or carbon ion beam radiation therapy
• Doxorubicin and ifosfamide may prove active in chondrosarcoma, especially in high-grade lesions, and gemcitabine in combination with docetaxel has also been reported to be effective

Sarcoma European Latin-American Network (SELNET) guidelines state that atypical cartilaginous tumors/grade I chondrosarcoma of long bones can be managed with intralesional extended curettage (large cortical window, high-speed burr) with or without local adjuvant therapy (eg, phenol or cryotherapy) and reconstruction with cement or bone graft.[27]

Grade II and III chondrosarcoma, as well as chondrosarcomas of any grade that are located in the pelvis or axial skeleton, should be surgically excised with wide margins.