Orthopedics

Feature Article 

Chondrosarcomas Revisited

Andreas F. Mavrogenis, MD; Marco Gambarotti, MD; Andrea Angelini, MD; Emanuela Palmerini, MD; Eric L. Staals, MD; Pietro Ruggieri, MD, PhD; Panayiotis J. Papagelopoulos, MD, DSc

Abstract

Chondrosarcomas are malignant bone tumors with pure hyaline cartilage differentiation; myxoid changes, calcification, or ossification may be present. Several subtypes of chondrosarcomas exist. Behavior patterns vary, ranging from slow-growing nonmetastasizing lesions to aggressive metastasizing sarcomas. Symptoms are usually mild, with duration ranging from several months to years, and usually consist of persistent, dull, aching pain or palpable masses. Radiographic findings include bone expansion with cortical thickening, radiolucent areas with variably distributed punctate or ring-like matrix calcifications, cortical erosion or destruction, endosteal scalloping, and scant or absent periosteal reaction; extension into the soft tissue may be present. Histological differential diagnosis from benign cartilaginous lesions can be achieved by increased cellularity, enlarged plump nuclei, binucleated cells, hyperchromatic nuclear pleomorphism, and permeation of cortical or medullary bone. Atypia is usually mild to moderate; necrosis and mitoses can be seen, particularly in high-grade lesions. Adequate surgery is the mainstay of treatment.

High-grade and pelvic chondrosarcomas are best managed with wide resection. Because of the low metastatic potential and low local recurrence rate noted with intralesional surgery, low-grade chondrosarcomas can be treated with curettage (with or without treatment of the defect cavity) with a local adjuvant, such as phenol or cryotherapy. Adjuvant chemotherapy may be considered for mesenchymal and dedifferentiated chondrosarcomas. Radiation therapy can be considered after incomplete resection or if resection is not feasible or would cause unacceptable morbidity.

Abstract

Chondrosarcomas are malignant bone tumors with pure hyaline cartilage differentiation; myxoid changes, calcification, or ossification may be present. Several subtypes of chondrosarcomas exist. Behavior patterns vary, ranging from slow-growing nonmetastasizing lesions to aggressive metastasizing sarcomas. Symptoms are usually mild, with duration ranging from several months to years, and usually consist of persistent, dull, aching pain or palpable masses. Radiographic findings include bone expansion with cortical thickening, radiolucent areas with variably distributed punctate or ring-like matrix calcifications, cortical erosion or destruction, endosteal scalloping, and scant or absent periosteal reaction; extension into the soft tissue may be present. Histological differential diagnosis from benign cartilaginous lesions can be achieved by increased cellularity, enlarged plump nuclei, binucleated cells, hyperchromatic nuclear pleomorphism, and permeation of cortical or medullary bone. Atypia is usually mild to moderate; necrosis and mitoses can be seen, particularly in high-grade lesions. Adequate surgery is the mainstay of treatment.

High-grade and pelvic chondrosarcomas are best managed with wide resection. Because of the low metastatic potential and low local recurrence rate noted with intralesional surgery, low-grade chondrosarcomas can be treated with curettage (with or without treatment of the defect cavity) with a local adjuvant, such as phenol or cryotherapy. Adjuvant chemotherapy may be considered for mesenchymal and dedifferentiated chondrosarcomas. Radiation therapy can be considered after incomplete resection or if resection is not feasible or would cause unacceptable morbidity.

Drs Mavrogenis and Papagelopoulos are from the First Department of Orthopaedics, ATTIKON University Hospital, Athens University Medical School, Athens, Greece; Dr Gambarotti is from the Department of Pathology, Dr Palmerini is from the Department of Oncology, and Drs Angelini, Staals, and Ruggieri are from the Department of Orthopaedics, Istituto Ortopedico Rizzoli, Bologna, Italy.

Drs Mavrogenis, Gambarotti, Angelini, Palmerini, Staals, Ruggieri, and Papagelopoulos have no relevant financial relationships to disclose.

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Correspondence should be addressed to: Andreas F. Mavrogenis, MD, First Department of Orthopaedics, ATTIKON University Hospital, Athens University Medical School, 41 Ventouri St,15562 Holargos, Athens, Greece (afm@otenet.gr).

Posted Online: March 07, 2012

Chondrosarcomas are malignant bone tumors with pure hyaline cartilage differentiation; myxoid changes, calcification, or ossification may be present. They are the third most common primary malignant tumors of bone after myeloma and osteosarcoma, representing approximately 25% of all primary bone tumors.1,2 They affect people of all ages, although they are more common in the fifth or sixth decades of life, with a slight preference for men (1.5–2:1). Chondrosarcomas are rare in children; when they occur, they tend to be aggressive. Although any bone can be affected, the most common sites are the pelvic and shoulder girdles, the proximal part of the long bones, the ribs, the scapulas, and the sternum. Primary chondrosarcomas are rare (<1%) in the spine and craniofacial bones, and unusual (approximately 1%) in the small bones of the hands and feet.1,3,4

Clinical and Imaging Presentation

The presentation of chondrosarcomas depends on the grade of the tumor. In most cases, symptoms are mild with long duration, ranging from several months to years, and usually consist of persistent dull, aching pain or palpable masses. A high-grade, fast-growing tumor can present with excruciating pain. Pelvic tumors present with urinary frequency or obstruction or may masquerade as groin muscle pulls.5,6

Radiographic findings include bone expansion with cortical thickening, radiolucent areas with variably distributed punctate or ring-like matrix calcifications, cortical erosion or destruction, endosteal scalloping, and scant or absent periosteal reaction. Extension into the soft tissue may be present. The degree of organization of the matrix calcification may be correlated with the grade of the tumor. Aggressive tumors contain irregular calcifications and often have large areas showing no calcification. Well-differentiated lesions tend to have more developed matrices, typical rings, and arc calcifications. When endosteal scalloping involves more than two-thirds the normal thickness of the cortex, it is useful in distinguishing chondrosarcoma from enchondroma; an exception exists in lesions of the hands and feet where enchondromas may cause considerable cortical thinning. In general, the presence of cortical destruction or a soft tissue mass and destruction of matrix calcification that was previously visible in an enchondroma indicates malignancy.7,8

Computed tomography (CT) is helpful in identifying endosteal scalloping, cortical destruction, and matrix calcification in lesions that appear entirely lucent on radiographs. Magnetic resonance imaging (MRI) is useful in demonstrating the intramedullary and soft tissue extension of the lesion and to assess the thickness of the cartilaginous cap of osteochondromas (<2 cm in adults) to identify chondrosarcoma transformation. Magnetic resonance imaging typically demonstrates lobulated lesions of low-signal intensity on T1-weighted MRIs and high-signal intensity on T2-weighted MRIs. Lobules are commonly separated by septa of low-signal intensity. Chondrosarcomas show variable patterns of enhancement after the administration of contrast material.8–10 Chondrosarcomas typically show significantly increased radioisotope uptake on bone scan, but differentiation from chondromas (osteochondromas or enchondromas) is unreliable; increased uptake may indicate metabolic activity in a chondroma or malignant transformation. However, in the absence of increased uptake, malignancy is unlikely.9–13

Histology

On gross examination, chondrosarcomas tend to have a translucent, blue-gray or white color corresponding with the presence of hyaline cartilage. A lobular growth pattern is a consistent finding. Focal calcification, myxoid or mucoid degeneration, or necrosis may be observed. At low magnification, chondrosarcomas show abundant blue-gray cartilage matrix production and irregularly shaped cartilage lobules varying in size and shape. These lobules may be separated by fibrous bands or permeate bony trabeculae. Histological differential diagnosis from benign cartilaginous lesions can be achieved by increased cellularity, enlarged plump nuclei, binucleated cells, hyperchromatic nuclear pleomorphism, and permeation of cortical or medullary bone. The extent of atypia is usually mild to moderate; necrosis and mitoses can be seen, particularly in high-grade lesions.

The histological criteria for diagnosing chondrosarcomas in the small bones of the hands and feet are different. Increased cellularity, binucleated cells, hyperchromasia, and myxoid change may be present in enchondroma in this location. The most significant histological feature of chondrosarcoma involving the small bones is permeation through the cortex into soft tissue and a permeative pattern in the cancellous bone.3,11

Classification and Grading

Chondrosarcomas are classified as primary (>90%) when they arise de novo or as secondary (<10%) when they occur in preexisting benign cartilage defects, such as osteochondromas or enchondromas. They are further classified as central (in the intramedullary canal) or peripheral (on the bone surface); they rarely (<2%) arise as periosteal or juxtacortical lesions.3,6 Although most chondrosarcomas are pathologically classified as conventional (80%–85%), several subtypes exist, which differ in location, appearance, treatment, and prognosis. These include clear cell (1%–2%), myxoid (8%–10%), mesenchymal (3%–10%), and dedifferentiated (5%–10%) chondrosarcomas.3,6,11

Chondrosarcomas are usually graded on a scale of 1 to 3 based primarily on nuclear size, nuclear staining (hyperchromasia), and cellularity.7,11,14,15 Histological grading is intended to reflect the aggressiveness of the lesion, with grade 1 tumors designated as low grade (Figure 1) and grades 2 and 3 as high grade (Figure 2).15 Grade 1 tumors are moderately cellular and contain hyperchromatic plump nuclei of uniform size. Binucleated cells are occasionally present. The cytology is similar to enchondroma; borderline cartilaginous lesions have been classified as cellular or atypical enchondromas, or chondrosarcomas grade 1/2. Grade 2 tumors are more cellular and contain a greater degree of nuclear atypia, hyperchromasia, and nuclear size. Grade 3 tumors are more cellular, pleomorphic, and atypical than grade 2 tumors; mitoses are easily detected.3,6 Occasionally, various histological grades coexist in the same tumor, especially in recurrences.3,11 Nevertheless, considerable controversy exists regarding the low reliability of the pathological and imaging grading of chondrosarcomas.16

Radiograph (A) and computed tomography scan (B) showing a grade 1 chondrosarcoma at the proximal femoral diaphysis. Photomicrograph showing increased cellularity compared with enchondroma, some degree of cytologic atypia, and permeation between host bony trabeculae (hematoxylin-eosin stain ×4) (C).

Figure 1: Radiograph (A) and computed tomography scan (B) showing a grade 1 chondrosarcoma at the proximal femoral diaphysis. Photomicrograph showing increased cellularity compared with enchondroma, some degree of cytologic atypia, and permeation between host bony trabeculae (hematoxylin-eosin stain ×4) (C).

Radiograph (A) and computed tomography scan (B) showing a grade 3 chondrosarcoma at the proximal femoral diaphysis. Photomicrograph showing increased cellularity, marked atypia, and pleomorphism; mitosis and necrosis may be present (hematoxylin-eosin stain ×20) (C).

Figure 2: Radiograph (A) and computed tomography scan (B) showing a grade 3 chondrosarcoma at the proximal femoral diaphysis. Photomicrograph showing increased cellularity, marked atypia, and pleomorphism; mitosis and necrosis may be present (hematoxylin-eosin stain ×20) (C).

Primary Chondrosarcoma

Primary chondrosarcoma arises de novo in a previously normal bone. It accounts for approximately 20% of all malignant bone tumors and >90% of all chondrosarcomas.6 More than 80% of primary chondrosarcomas are conventional, and >60% are grade 1 or 2.3,6 The prognosis is generally good; histological grade, large tumor size, older age, and inadequate surgery have been correlated with local recurrence and metastasis.2,3 The 5-year survival rate is 88% for patients with grade 1 and 57% for patients with grade 2 and 3 tumors; the local recurrence and metastasis rates are 20% and 14%, respectively. Approximately 10% of tumors that recur have an increase in the degree of malignancy.6

Secondary Chondrosarcoma

Secondary chondrosarcomas occur in preexisting benign cartilage lesions, such as osteochondromas (secondary peripheral chondrosarcomas) (Figure 3) or enchondromas (secondary central chondrosarcomas). The reported incidence is 0.4% to 2.2% in patients with a solitary osteochondroma or enchondroma, whereas the incidence increases to 27.3% in patients with hereditary multiple exostoses,17–19 30% to 50% in patients with Ollier’s disease, and up to 100% in patietns with Maffucci syndrome.20–24 Primary conventional and secondary peripheral chondrosarcomas may differ in their genetic makeup, as reflected by a clear difference in the loss of heterozygosity pattern, loss of heterozygosity incidence, deoxyribonucleic acid (DNA) ploidy status, and cytogenetic aberrations.25

Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a secondary peripheral chondrosarcoma at the iliac wing of a patient with hereditary multiple exostoses. Photomicrograph showing a cartilaginous cap >2 cm in maximum thickness. The cap has a lobular architecture with clustered chondrocytes at the periphery of the lobules; myxoid changes may be present (hematoxylin-eosin stain ×2) (D).

Figure 3: Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a secondary peripheral chondrosarcoma at the iliac wing of a patient with hereditary multiple exostoses. Photomicrograph showing a cartilaginous cap >2 cm in maximum thickness. The cap has a lobular architecture with clustered chondrocytes at the periphery of the lobules; myxoid changes may be present (hematoxylin-eosin stain ×2) (D).

Patients with secondary chondrosarcoma are generally younger than those with primary chondrosarcoma. Changes in clinical symptoms in patients with known precursor lesions herald the development of chondrosarcomas. Chondrosarcomas secondary to osteochondromas show a thick (>2 cm) lobulated cartilage cap, with cystic cavities.25 Secondary chondrosarcomas are generally low-grade tumors, with similar prognosis to conventional chondrosarcoma that depends on the location and grade of the tumor.26

Periosteal or Juxtacortical Chondrosarcoma

Periosteal or juxtacortical chondrosarcoma occurs on the surface of bone, and accounts for <2% of all chondrosarcomas.27,28 The distal femur is the most common location. Periosteal chondrosarcoma tends to affect young adults in the second to fourth decades of life.27,29 Periosteal chondroma and periosteal osteosarcoma are the most difficult tumors to differentiate.27,30 The size of the tumor has been reported to be the most reliable indicator to distinguish from periosteal chondroma.31 On imaging, the lesion appears to involve the cortex with indistinct margins (Figure 4). It is generally larger than periosteal chondroma (>5 cm), covered by elevated periosteum, and pasted on the cortical bone showing variable erosion.9,32 Surgical resection with wide margins is the primary treatment for periosteal chondrosarcoma. The prognosis is generally good.27,30,33 The reported incidence of local recurrence varies from 13% to 28%.27,32,33 The 5-year local recurrence and metastasis rates are 30% and 17%, respectively; both are significantly higher for patients treated with wide resection or amputation. No significant difference has been observed for the 5-year metastasis-free survival rate between patients with grade 1 and grade 2 tumors.34

Radiograph (A) and T2-weighted magnetic resonance image (B) showing a periosteal chondrosarcoma at the proximal humerus. Photomicrograph showing lobules of the tumor permeating the surrounding soft tissue; myxoid change in the matrix may be present (hematoxylin-eosin stain ×4) (C).

Figure 4: Radiograph (A) and T2-weighted magnetic resonance image (B) showing a periosteal chondrosarcoma at the proximal humerus. Photomicrograph showing lobules of the tumor permeating the surrounding soft tissue; myxoid change in the matrix may be present (hematoxylin-eosin stain ×4) (C).

Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a low-grade variant of chondrosarcoma.35,36 Histologically, it is characterized by bland clear cells and hyaline cartilage.3,37 Most patients are between ages 25 and 50 years. A male predominance exists. Clinical symptoms may be present for >1 to 5 years.35–38 Clear cell chondrosarcoma has a predilection for the epiphyseal ends of long bones.9 Radiographically, it usually presents as a well-defined lytic lesion in the epiphysis of a long bone, occasionally with a sclerotic rim and stippled radiodensities that may resemble chondroblastoma or avascular necrosis (Figure 5).9 The prognosis is generally good after wide surgical resection. Inadequate surgery is associated with a recurrence rate of up to 86% and late metastases, usually to the lungs and other skeletal sites.35,39,40

Computed tomography scan (A) and T1-weighted magnetic resonance image (B) showing a clear cell chondrosarcoma at the proximal tibial epiphysis. Photomicrograph showing proliferation of cells, with abundant optically empty or eosinophilic cytoplasm and centrally located vescicular nuclei. Production of immature bone by tumor cells is a peculiar feature. Scattered giant cells (hematoxylin-eosin stain ×20) (C).

Figure 5: Computed tomography scan (A) and T1-weighted magnetic resonance image (B) showing a clear cell chondrosarcoma at the proximal tibial epiphysis. Photomicrograph showing proliferation of cells, with abundant optically empty or eosinophilic cytoplasm and centrally located vescicular nuclei. Production of immature bone by tumor cells is a peculiar feature. Scattered giant cells (hematoxylin-eosin stain ×20) (C).

Myxoid Chondrosarcoma

Primary skeletal myxoid chondrosarcoma is composed almost entirely (95%) of a myxoid matrix with minimal hyaline cartilage formation (Figure 6). The term has been used to designate a conventional chondrosarcoma with prominent myxoid degeneration or a myxoid sarcoma that is identical histologically to extraskeletal myxoid chondrosarcoma; however, extraskeletal and skeletal myxoid chondrosarcoma represent 2 distinct entities in the chondrosarcoma family of tumors.41 Skeletal myxoid chondrosarcoma may be distinguished from chondromyxoid fibroma mainly by the sharply demarcated radiographic area of bone destruction and histologically by the lack of stellate and spindle cells randomly arranged in a fibromyxoid stroma and accompanied by multinucleated giant cells.42 Skeletal myxoid chondrosarcoma appears to represent a variant of conventional chondrosarcoma because it has similar clinicopathological features, including patient age, location, ultrastructural, clinical behavior, and prognosis.14,41

Radiograph (A) and T2-weighted magnetic resonance image (B) showing a myxoid chondrosarcoma at the femoral diaphysis. Photomicrograph showing a typical myxoid background. The lesion is more cellular than grade 1 chondrosarcoma, and the cells are slightly more atypical (hematoxylin-eosin stain ×10) (C).

Figure 6: Radiograph (A) and T2-weighted magnetic resonance image (B) showing a myxoid chondrosarcoma at the femoral diaphysis. Photomicrograph showing a typical myxoid background. The lesion is more cellular than grade 1 chondrosarcoma, and the cells are slightly more atypical (hematoxylin-eosin stain ×10) (C).

Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is characterized by a bimorphic pattern composed of undifferentiated small, round cells and islands of well-differentiated hyaline cartilage. The peak incidence is in the second and third decades of life.43–45 In contrast to conventional chondrosarcoma, the craniofacial bones (especially the jaw bones), ribs, ilium, and vertebrae are the most common sites.46–49 Multiple bone involvement has been reported.43 Radiographically, skeletal lesions are primarily lytic and destructive with poor margins, not significantly differing from conventional chondrosarcoma in most cases. Cortical destruction with extraosseous extension of soft tissue is common.9 Histologically, the typical biphasic pattern is composed of undifferentiated small, round cells admixed with islands of hyaline cartilage (Figure 7). The amount of cartilage varies. The cartilage may be distinct from the undifferentiated component or blend gradually with it. In the undifferentiated areas, the small, round cells typically simulate Ewing’s sarcoma and a hemangiopericytomatous vascular pattern.50,51 The prognosis is poor and the role of chemotherapy unclear; the tumor is malignant, with a strong tendency toward local recurrence and distant metastasis.6,43,46

Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a mesenchymal chondrosarcoma at the pelvis. Photomicrograph showing moderately cellular chondroid areas juxtaposed to a proliferation of small blue round undifferentiated malignant cells (hematoxylin-eosin stain ×10) (D).

Figure 7: Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a mesenchymal chondrosarcoma at the pelvis. Photomicrograph showing moderately cellular chondroid areas juxtaposed to a proliferation of small blue round undifferentiated malignant cells (hematoxylin-eosin stain ×10) (D).

Dedifferentiated Chondrosarcoma

Dedifferentiated chondrosarcoma is 1 of the most malignant primary bone tumors. The average age of presentation is the fifth and sixth decade of life.52–55 It is characterized by 2 distinct histopathological components: a well-differentiated benign chondral lesion or chondrosarcoma (any grade) sharply juxtaposed with a high-grade noncartilaginous component (Figure 8).56,57 An abrupt transition typically occurs between the 2 tissue types.56 The noncartilaginous component is generally osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma. Dedifferentiation to leiomyosarcoma, giant cell tumor, and, rarely, clear-cell chondrosarcoma or rhabdomyosarcoma has also been reported.39,58,59

Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a dedifferentiated chondrosarcoma at the pelvis. Photomicrograph showing abrupt transition between a low-grade chondrosarcoma (left) and a high-grade spindle cell sarcoma (right) (hematoxylin-eosin stain ×10) (D).

Figure 8: Radiograph (A), computed tomography scan (B), and T2-weighted magnetic resonance image (C) showing a dedifferentiated chondrosarcoma at the pelvis. Photomicrograph showing abrupt transition between a low-grade chondrosarcoma (left) and a high-grade spindle cell sarcoma (right) (hematoxylin-eosin stain ×10) (D).

The rate of dedifferentiation is 13% to 15% in central chondrosarcomas compared with 4% to 5% in peripheral chondrosarcomas.53,55,60 Dedifferentiation may occur as late as 20 years after primary resection of a chondrosarcoma.61 Radiographically, dedifferentiation is suggested by a sharply demarcated area of aggressive bone destruction associated with an underlying cartilaginous lesion and an extraosseous soft tissue mass. Not uncommonly, radiographs show no evidence of chondral matrix mineralization.55,62–64 Three radiographic types of dedifferentiated chondrosarcoma have been described. In type 1, the radiographic appearance is the same as for a central chondrosarcoma, with the addition of a region with aggressive bone destruction. In type 2, lesions resemble an underlying benign enchondroma but also have destructive changes or a large soft tissue masses. In type 3, lesions are not distinctive radiographically and present as an aggressive destructive bone lesion.55

Wide resection is mandatory in patients with dedifferentiated chondrosarcoma.1,2,65,66 Poor survival and no difference in overall survival between patients managed with surgery and those managed with combined surgery and chemotherapy have been observed.52,53,67 Chemotherapy is usually added to the treatment whenever the dedifferentiated component is chemosensitive and the patient is in good general condition. Radiation therapy may be administered for sites that are difficult to access surgically and for palliation of local symptoms.65 Despite aggressive therapy, the 2-year survival rate is <20%.53

Surgical Treatment

Chondrosarcomas are a surgical disease; the role of chemotherapy and radiation therapy is limited. High-grade (grade 2 and 3) chondrosarcomas are best managed with wide resection.1,2,66,68 Chondrosarcomas of the pelvis and spine can be particularly difficult to treat due to the size of the tumor and its relationship to important adjacent structures, such as the bladder or spinal cord and intralesional or marginal resection margins. Local recurrences are the highest in this group of patients with axial tumors.1,69,70 Because of the low metastatic potential and low local recurrence rate reported with intralesional surgery for low-grade (grade 1) chondrosarcomas, a trend away from wide resection has occurred in these tumors. In these cases, treatment involves curettage of the tumor through a cortical window, extending the curettage with a high-speed burr to the surrounding bone, with or without treatment of the defect cavity with a local adjuvant, such as phenol or cryotherapy. The bony defect can then be reconstructed with allograft or autologous bone grafting or polymethyl-methacrylate.69–72 Adjuvant cryosurgery of the tumor cavity with liquid nitrogen or other freezing modalities may decrease the local recurrence rate in patients with low-grade chondrosarcomas, but it increases complications, such as fracture of the bone and injury to surrounding neurological structures.73 In cases of low-grade chondrosarcomas with aggressive radiological findings (eg, soft tissue mass, cortical destruction, or expansion of a long bone), large tumor size, intra-articular or pelvic locations, wide resection remains the treatment of choice.69–72,74

Nonsurgical Treatment

Chemotherapy

Chemotherapy is not effective in chondrosarcomas, especially in the most common conventional and clear cell types. Possible explanations of resistance are slow growth, expression of the multidrug-resistance-1 gene P-glycoprotein, large amount of extracellular matrix, and poor vascularity impending the access of chemotherapeutic drugs.74–77 Currently, 2 non-randomized, open-label phase II clinical trials are studying the effect of chemotherapeutic agents on chondrosarcoma: 1 trial is investigating the effect of pemetrexed, a multitargeted antifolate that inhibits the formation of precursor purine and pyrimidine nucleotides in patients with grades 2 and 3 chondrosarcomas.78 Another trial recruited patients with an unresectable or locally recurrent chondrosarcoma to investigate the response to gemcitabine, followed by docetaxel.79

The role of adjuvant chemotherapy for dedifferentiated chondrosarcoma remains unclear.53,54,67,76 For mesenchymal chondrosarcoma, a role exists for doxorubicin-based combination chemotherapy that may also be used for palliation of meta-static disease.45,74,77

Radiation Therapy

Chondrogenic tumors are considered relatively radioresistant. A possible explanation is the slow tumor growth.74 Some research has shown that p16 (ink4a), 1 of the major tumor suppressor proteins that regulates the cell cycle, could play a role in radiation resistance in chondrosarcoma cells.80 Therefore, restoring p16 expression could increase the radiosensitivity of chondrosarcomas. Another possible way to enhance the radiosensitivity of chondrosarcomas is to facilitate apoptotic pathways by silencing antiapoptotic genes. Some promising results have been obtained with this method in grade 2 human chondrosarcoma cell lines.81 The combination of radiotherapy with razoxane, an antiangiogenic topoisomerase II inhibitor, seems to result in a better response than with radiotherapy alone.82

Radiation therapy can be considered (1) after incomplete resection, aiming at maximal local control (curative); (2) if resection is not feasible or would cause unacceptable morbidity (palliative), especially for patients with mesenchymal chondrosarcomas, because these tumors are considered more radiosensitive; and (3) when surgery would cause major unacceptable morbidity or is technically impossible, such as for skull-base chondrosarcomas.74

Stereotactic Radiosurgery

Stereotactic radiosurgery has been a successful treatment for skull-base83,84 and spinal85 chondrosarcomas, especially for those small in size, reaching a 5-year local tumor control of 80%.83

Proton Therapy

Proton radiotherapy has been used for ocular melanoma, chordoma, and chondrosarcoma of the skull base or cervical spine.86 Compared with conventional radiotherapy, proton radiotherapy seems more effective in skull-base chondrosarcomas.87 Promising results were reported after carbon ion radiotherapy in skull-base chondrosarcomas, with a 4-year local control rate of 90%.88

Targeted Treatments

Protein Tyrosine Kinases Inhibitors

Few studies have evaluated the expression of protein tyrosine kinases inhibitors platelet-derived growth factor receptor-α (PDGFR-α), PDGFR-β, and tyrosine kinase receptor in conventional chondrosarcomas. Coexpression of PDGFR-α and PDGFR-β was found, with greater protein expression and higher phosphorylation levels for PDGFR-β; an autocrine/paracrine activation loop of the corresponding receptors was suggested because no activating mutations or abnormal genomic profiles were detected.89,90 Immunohistochemistry expression of PDGFR-α has been associated with a higher histological grade and shorter survival time in patients with conventional chondrosarcoma.90 Other tyrosine kinases inhibitors, such as imatinib and dasatinib, and mitogen-activated protein kinases inhibitors, such as perifosine, have also been studied in metastatic and locally advanced chondrosarcomas.90,91

Monoclonal Trail Antibodies

Apomab is a monoclonal antibody against the tumor necrosis factor–related apoptosis-inducing ligand death receptor 5. It has been investigated in patients with advanced chondrosarcoma.92 Preliminary results showed stable disease for approximately 50% of the studied patients.93

Indian Hedgehog Inhibitors

Indian hedgehog signaling plays an important role in growth-plate chondrocyte proliferation and in the development of benign cartilage tumors, such as enchondromas and osteochondromas.94,95 In chondrosarcomas, treatment with recombinant hedgehog increased the proliferation of tumor cells, whereas treatment with Indian hedgehog inhibitors, such as triparanol, reduced chondrosarcoma cell proliferation and tumor growth.96 In addition, decreased expression of Indian hedgehog downstream targets during tumor progression has been identified in peripheral chondrosarcoma.97 However, increased side effects of Indian hedgehog inhibitors have limited their clinical applications.96

Parathyroid Hormone-like Hormone Blockade

Increased activity of parathyroid hormone-like hormone signaling has been observed in enchondromas and central and peripheral chondrosarcomas; activity has been associated with higher grades of chondrosarcomas.98–102 Parathyroid hormone-like hormone blockade could be used to decrease the proliferation of chondrosarcomas. Bcl-2 antisense therapy might be useful in this perspective, because Bcl-2 is the downstream effector of parathyroid hormone-like hormone and is expressed in peripheral and high-grade central chondrosarcomas.98,99 In addition, a monoclonal murine antiparathyroid hormone-like hormone antibody–promoted chondrogenic differentiation and accelerated apoptosis in chondrosarcoma cells, due to down regulation of its downstream target Bcl-2.103

Antiangiogenesis Therapy

Tumor vascularization; increased activity of matrix metalloproteinases 1, 2, 9, and 13; and overexpression of the vascular endothelial growth factor A and cathepsins B and L increase with increasing histological grade of chondrosarcomas.104–106 Some authors showed that a combination of an antiangiogenic factor (plasminogen-related protein B) with a marine-derived chemotherapeutic molecule (ecteinascidin-743) significantly inhibited tumor microvessel formation and increased tumor necrosis compared with single-drug treatment.107 In addition, prostaglandin G/H synthase 2, a cyclooxygenase-2 mediator of angiogenesis, has been shown to be expressed in chondrosarcomas, with no correlation with histological grade.108 This finding suggests that selective cyclooxygenase-2 inhibitors might be effective in chondrosarcomas.

Bisphosphonates

Antitumor activity by several bisphosphonates has been demonstrated in human chondrosarcoma cell lines.109–111 Zoledronic acid has been tested in vivo and in vitro in a rat chondrosarcoma model and showed inhibition of tumor-cell proliferation, induction of nonapoptotic cell death, and decreased tumor progression.109 Alendronate showed a dose- and time-dependent inhibitory effect on the invasion and migration of human chondrosarcoma cells, and decreased the activity and messenger ribonucleic acid levels of matrix metalloproteinase-2.111 Minodronate, a novel third-generation, nitrogen-containing bisphosphonate, inhibited cell viability and induced S-phase arrest and apoptosis in chondrosarcoma cell lines.110

Histone Deacetylase Inhibitors

Histone acetylation and deacetylation play a key role in the regulation of chondrocytic differentiation. Depsipeptide, a histone deacetylase inhibitor, induced cell cycle arrest, apoptosis, chondrocytic maturation, and inhibited tumor growth in a xenograft chondrosarcoma murine model.112

Hormonal Therapy

Estrogen-mediated signaling is essential in cartilaginous proliferation and differentiation in the growth plate, and regulation of longitudinal skeletal growth.113 Aromatase is an enzyme that mediates the last in a series of steps for estrogen synthesis. In a study, the presence of estrogen receptors and functional aromatase activity were identified in chondrosarcoma samples; subsequently, growth of chondrosarcoma cells was stimulated by estrogen or androstenedione, whereas it was inhibited by an aromatase inhibitor.114 Another study showed expression of estrogen receptors α and β in benign and malignant cartilaginous tumors. Both receptors were expressed more frequently in low-grade than in high-grade chondrosarcomas.115

Outcomes

The 5-year survival rate for patients with grade 1 chondrosarcomas is 90% to 100%, whereas the rate decreases to 60% and 30% to 40% for patients with grade 2 and 3 tumors, respectively.3,52,53,67,116–118 Survival rates generally stabilize 10 years after diagnosis and treatment.118 The 5-year survival rates according to the histological type range from 0% (dedifferentiated chondrosarcoma) to 48% to 52% (mesenchymal chondrosarcoma), 70% (conventional chondrosarcoma), 71% (myxoid chondrosarcoma), 87% to 93% (juxtacortical chondrosarcoma), and 100% (clear cell chondrosarcoma).53,118–121 With current treatment strategies, including local adjuvant therapy, low-grade tumors rarely metastasize or recur postoperatively.2,3,52,53,67,116–118 In contrast, high-grade tumors have a higher recurrence rate and are prone to pulmonary metastases; 10% to 33% of grade 2 and approximately 70% of grade 3 chondrosarcomas metastasize.66,122 Grade 1 chondrosarcomas can recur after 10 to 20 years, whereas grade 2 recur within 5 years, and grade 3 tumors often recur within 1 year.1,2,6 Therefore, long-term follow-up with evaluation of the site of local disease and pulmonary imaging should be performed for at least 10 years postoperatively.118

Recurrent chondrosarcoma is often more aggressive than the original lesion, and the histological grade is often higher. Approximately 10% of recurrent chondrosarcomas have an increase in histological grade; this is more common (14% to 25%) for grade 2 chondrosarcomas at initial presentation.70,123 Occasionally, various histological grades coexist in the same tumor.

Prognostic Factors

Age, sex, tumor location and size, surgical stage and margins, local recurrence, and several histological parameters, including grade, tumor necrosis, mitotic count, and myxoid matrix, have been associated with the survival, recurrence, and metastasis of patients with chondrosarcomas. Age 50 years or younger, female sex, location in the appendicular skeleton, tumor size <10 cm, low histological grade, local surgical stage, and wide-margin resections have been associated with better prognosis and longer survival. However, on multivariate analyses, grade, stage, location, and margins were significant prognostic factors.3,66,118 In general, a patient who has a large grade 3 pelvic lesion with an aneuploid pattern and a high mean DNA index is at high risk for metastasis and death despite treatment. Furthermore, if the margins are violated when the tumor is removed, the risk is likely to increase.1

The grade of the tumor is an important prognostic factor for local recurrence and overall survival of patients with chondrosarcomas.1,70,123,124 In high-grade chondrosarcomas, local recurrence compromises survival.15 However, controversy exists when grade 1 tumors are considered.125,126 For low-grade chondrosarcomas in the axial and appendicular skeleton, local recurrence is associated with lower overall survival, and wide resection is recommended.125 For low-grade chondrosarcomas in the long bones, if the local recurrence is solitary, with no progression in grade, the treatment of choice is repeat intralesional resection, with or without local adjuvants; if soft tissue involvement exists, wide resection is recommended. For high-grade chondrosarcomas of any location, local recurrence should be treated with wide resection.74

Patients with axial chondrosarcomas of any grade have a worse prognosis than those with lesions of the appendicular skeleton.1,3,66,70,118,123 Another important prognostic factor for local outcome is the location of the tumor in the pelvis. Tumors that cross the sacroiliac joint have a higher incidence of local recurrence compared with those at other pelvic locations. This has been attributed to the inaccuracy of estimating the degree of tumor extension across the sacroiliac joint and the difficulty in performing osteotomies during resection.70

Studies confirm higher local recurrence rates in patients with inadequate resection margins.1,66,70,127–129 Although almost all authors agree that a wide resection is mandatory in low-grade extracompartmental and high-grade chondrosarcomas, no consensus exists about the adequate surgical margins for low-grade intracompartmental tumors.1,3,66,126 For low-grade chondrosarcomas, some authors advocate wide resection,8,14 whereas others believe intralesional resection augmented with local adjuvants, such as liquid nitrogen, phenol, electrocautery, and argon-beam laser, is adequate.126,130 Peripheral chondrosarcomas show a tendency to inadequate margins compared with central lesions because of the larger size of peripheral tumors.70 In a study of 61 patients with grade 1 or 2 secondary peripheral chondrosarcoma of the pelvis, a 3% local recurrence rate was found after wide resection compared with 23% after inadequate excision.70 In another study, the majority of patients with low-grade intracompartmental chondrosarcomas of the pelvis had a misdiagnosis or recurrence of higher-grade disease; these authors concluded that curettage may be performed for low-grade intracompartmental chondrosarcomas of the pelvis, with the understanding that a percutaneous biopsy may misrepresent the histological grade and that curettage may result in a higher risk of recurrence.72

For patients with dedifferentiated chondrosarcomas, metastatic disease at diagnosis, malignant fibrous histiocytoma dedifferentiation, and a high percentage of dedifferentiated component were related to poorer outcomes. No difference existed with respect to the location of the dedifferentiated chondrosarcoma in the axial or appendicular skeleton.53

Conclusion

The term chondrosarcoma describes a group of tumors with diverse features and behavior patterns, ranging from low-grade, slow-growing lesions with low metastatic and local recurrence potential to aggressive metastasizing sarcomas. Recognition of the various types of chondrosarcoma is important. Tumor grade, location, and adequacy of resection are the most important predictors of outcome. Surgery is the mainstay of treatment. Although convincing evidence is lacking, adjuvant chemotherapy may be considered for mesenchymal and dedifferentiated chondrosarcoma. Radiation therapy may be considered for the treatment of chondrosarcomas of the skull base and the spine, whereas modern radiation techniques could further improve the outcome for patients with tumors in locations that are difficult to access surgically.

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Authors

Drs Mavrogenis and Papagelopoulos are from the First Department of Orthopaedics, ATTIKON University Hospital, Athens University Medical School, Athens, Greece; Dr Gambarotti is from the Department of Pathology, Dr Palmerini is from the Department of Oncology, and Drs Angelini, Staals, and Ruggieri are from the Department of Orthopaedics, Istituto Ortopedico Rizzoli, Bologna, Italy.

Drs Mavrogenis, Gambarotti, Angelini, Palmerini, Staals, Ruggieri, and Papagelopoulos have no relevant financial relationships to disclose.

Correspondence should be addressed to: Andreas F. Mavrogenis, MD, First Department of Orthopaedics, ATTIKON University Hospital, Athens University Medical School, 41 Ventouri St,15562 Holargos, Athens, Greece (afm@otenet.gr).

10.3928/01477447-20120222-30

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