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Background

Chondrosarcomas are malignant tumors of the bone formed by malignant cartilage. These tumors present with pain in 75% of patients. Symptoms usually last about 33 months before diagnosis. Like osteosarcomas, there are many important variants, differing both in clinical and histological presentation. These variants are covered in the outline below. Extraskeletal chondrosarcomas are covered here.

Variants of Chondrosarcoma
Central
Peripheral
Dedifferentiated
Clear cell
Mesenchymal
Juxtacortical

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
INCIDENCE 11% of malignant bone tumors
AGE RANGE-MEDIAN

 

Central

Range 5-90 years
Peak 5-7th decades

Secondary
Peak in 4-5th decades
Juxtacortical
80%>20 years
Range 15-63 years of age
Mesenchymal
80% between 10-40 years
Range 5-74 years
Clear cell
Most in 3-4th decades
Range 14-84 years
Dedifferentiated
Most >50 years
Range 19-82 years
SEX (M:F) for classic central tumors
2:1

 

DISEASE ASSOCIATIONS CHARACTERIZATION
PARENTAL BONE CANCERS  


Parental cancer as a risk factor for bone cancer: a nation-wide study from Sweden.

Li X, Hemminki K.

Department of Biosciences at Novum, Karolinska Institute, 141 57 Huddinge, Sweden.

J Clin Epidemiol 2002 Feb;55(2):111-4 Abstract quote

We used the nation-wide Swedish Family-Cancer Database to analyze the risk for bone cancer in offspring by parental cancers and in siblings of bone cancer probands. Additionally, the risk of second cancer following childhood bone cancer was investigated.

In offspring, 1,190 bone cancers were diagnosed between years 1958 and 1996. Groups of offspring were compared by calculating standardized incidence ratios (SIRs) for bone cancer. Most bone cancer cases occurred sporadically. Parental breast (SIR 1.7) and prostate (SIR 1.7) cancers were associated with early-onset (<25 years) osteosarcoma in offspring, probably due to Li-Fraumeni syndrome. Giant cell sarcoma was increased by parental breast cancer (SIR 2.9), and early-onset chondrosarcoma by parental kidney cancers (SIR 6.8).

Bone cancers conveyed a high risk of second bone and connective tissue cancer.

 

PATHOGENESIS CHARACTERIZATION
H-RAS  

H-ras Oncogene Mutation in Dedifferentiated Chondrosarcoma: Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Analysis

Akio Sakamoto, etal.

Mod Pathol 2001;14:343-349 Abstract quote

Dedifferentiated chondrosarcomas, which are known for their poor prognosis, are characterized by conventional chondrosarcoma with high-grade anaplastic components. Activating mutations in ras genes are a common genetic abnormality in human malignancies.

The presence of point mutations at codons 12 and 13 of the H-ras gene was studied in 20 formalin-fixed paraffin-embedded chondrosarcomas, comprising 11 cases of conventional chondrosarcoma (six Grade 1 cases and five Grade 2 cases) and nine cases of dedifferentiated chondrosarcoma, using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing analysis.

H-ras mutations were only seen in two out of the nine cases of dedifferentiated chondrosarcoma (2/9, 22%) and they were not seen in any of the cases of conventional chondrosarcoma (0/11, 0%). Dedifferentiated chondrosarcomas had a worse prognosis than conventional chondrosarcomas (P < .01); among the patients with dedifferentiated chondrosarcomas, those with H-ras mutation (n = 2) tended to have a worse prognosis than those without (n = 7), although the difference was not statistically significant (P = 0.068).

Our results would seem to suggest that H-ras mutation may occur during the course of dedifferentiation and may also have some effect on malignant potential.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION
Radiographs  
Central tumors
Extensive intramedullary spread
Peripheral tumors
Masses that protrude from the cortex

 

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION
General-Primary chondrosarcomas

Pelvic bones most common site
Proximal femur
Proximal humerus
Distal femur
Ribs

Usually occur in the diaphysis or metaphysis
Cut sections show appearance of hyaline cartilage with blue or white color

Lobular pattern with areas of chalky calcifications common
Hemorrhagic necrosis in high grade tumors

Secondary
Tumors arising on preexisting benign cartilaginous lesions
Central
Central tumors may have extensive intramedullary spread
Peripheral
Form masses that protrude from cortex
Juxtacortical

<2% of all chondrosarcomas
Femur most common site
Long bone lesions have a predilection for the metaphysis, less likely the diaphysis

Cartilage type, eggshell or popcorn matrix calcifications
Underlying cortex is often sclerotic with a saucer shaped defect with a sharply defined border
Average size 11 cm

Mesenchymal

2% of all chondrosarcomas
Favors the maxilla, mandible, ribs, and vertebrae
Pelvis and femur

Lytic defect with stippled calcifications
Cortex destroyed in 50% of cases with associated soft tissue extension

Clear cell

2% of all chondrosarcomas
Epiphyses of long bones
Proximal femur and humerus, distal femur, and proximal tibia

Expansile osteolytic tumor with sharp interface between tumor and surrounding bone

Dedifferentiated

11% of all chondrosarcomas
Bones of the pelvis, proximal femur and humerus, distal femur, and ribs

Lytic intraosseous lesion or extraosseous soft tissue mass
Usually cortical perforation
Abrupt transition between chondroid tumor and dedifferentiated lytic component

 

HISTOLOGICAL TYPES CHARACTERIZATION
General-Primary chondrosarcomas

Irregularly shaped lobules of cartilage with variable size, often separated by narrow fibrous bands

Chondocytes arranged in clusters or groups, slightly enlarged nuclei and occasionally bizarre nuclei

Mitotic figures not found in grade 1 tumors but widely scattered in grade 2 tumors, and abundant in grade 3 tumors

Matrix varies from mature hyaline cartilage to myxoid stroma

Spindle cells may be present in grade 3 tumors

Sections taken from the edge show cartilage invading the marrow between trabeculae of bone-the permeation pattern

May have fingerlike extensions into the soft tissue

GRADING  
1
Chondrocytes with small, dense nuclei, some with slightly enlarged nuclei, rare multinucleated and binucleated
Stroma usually chondroid, with sparse myxoid areas
2
Less matrix with more cellular areas, especially around the periphery of the tumor
Chondrocyte nuclei are enlarged and vesicular or hyperchromatic
Usually multiple nuclei within lacunae
Frequently myxoid stroma
Variable areas of necrosis
3
Greater cellularity and nuclear pleomorphism compared to the grade 2 tumors
Sparse chondroid matrix and small amount of intercellular material which is myxoid
Neoplastic chondrocytes arranged in cords and clumps
Individual cells with stellate or irregular shapes
Nuclei spindled and vesicular, 5-10x normal
Juxtacortical
Well differentiated cartilaginous lobules, hyaline type
Microscopic extension into soft tissue common
Grade 3 tumors rare
Mesenchymal
Small round, oval to spindled neoplastic cells with irregular clumping of chromatin and small nucleoli
Variable mitotic rate
Cartilaginous areas are sparse
Vascular with hemangiopericytoma-like pattern
Clear cell
Lobular cartilaginous nests with clear cells
Mitotic figures rare
Matrix formation sparse with focal calcification
Aggressive clear cell chondrosarcomas: do distinctive characteristics exist?: a report of 4 cases.

Department of Pathology and Laboratory Medicine, Pathology Section, University of Parma, Via Gramsci 14, 43100 Parma, Italy.

Arch Pathol Lab Med. 2006 Nov;130(11):1673-9 Abstract quote

CONTEXT: Clear cell chondrosarcoma (CCC) is commonly considered to be a low-grade subtype of chondrosarcoma. However, a few cases of CCC behave as high-grade lesions (with early metastases or multiple/synchronous locations).

OBJECTIVE: To investigate morphologic features that can help predict the aggressiveness of these CCCs.

DESIGN: To investigate possible hallmarks of this aggressiveness, we are presenting the clinicopathologic features of 6 cases of CCC, 4 of which presented aggressive features and 2 low-grade behavior. The patients were 5 men and 1 woman; their ages ranged from 22 to 47 years. Histologic appearance, ultrastructure, and immunohistochemical expression of metalloproteinase 1 and 2 and their inhibitors were evaluated in all 6 cases.

RESULTS: Pain was the most common symptom; the lesions were located in the femur (4), humerus (2), and vertebral body (1), with 1 patient presenting a double/synchronous lesion. Although no major differences were detected using conventional light microscopy, an ultrastructural analysis--at variance with usual cases--showed a lack of superficial microvilli in more than 50% of neoplastic cells in the aggressive cases, therefore suggesting a less differentiated phenotype. In addition, metalloproteinase 2 was more diffusely expressed in the aggressive tumors than in the conventional CCCs, whereas p53 labeling was always negative.

CONCLUSIONS: The aggressive behavior of some CCCs may be, at least in part, correlated to a lesser degree of cell differentiation and to the expression of tumor cell proteins, such as metalloproteinase 2, which are able to favor neoplastic spreading.
Dedifferentiated

Chondrosarcoma component usually grade 1
Sharp junction between cartilaginous and noncartilaginous elements

Noncartilaginous component varies from fibrosarcoma, malignant fibrous histiocytoma, osteosarcoma, rhabdomyosarcoma, and angiosarcoma

ADDITIONAL VARIANTS  
DEDIFFERENTIATED  

Dedifferentiated Clear Cell Chondrosarcoma

Ricardo K. Kalil, M.D.; Carrie Y. Inwards, M.D.; K. Krishnan Unni, M.B., B.S.; Franco Bertoni, M.D.; Patricia Bacchini, M.D.; Doris E. Wenger, M.D.; Franklin H. Sim, M.D.

From the Division of Anatomic Pathology (R.K.K., C.Y.I., K.K.U., F.B., P.B.), the Department of Diagnostic Radiology (D.E.W.), and the Department of Orthopedic Surgery (F.H.S.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Am J Surg Pathol 2000;24:1079-1086 Abstract quote

Dedifferentiation, a change in the histologic character and clinical behavior of a tumor to a more immature and aggressive one, occurs in approximately 11% of all chondrosarcomas. The original lesion is usually a low-grade chondrosarcoma. Clear cell chondrosarcoma is a rare cartilaginous tumor of low-grade malignancy with a preference for the ends of long bones. It is usually curable by resection. Recurrence commonly follows inadequate surgery, and metastases to lung, brain, and bones can develop. However, dedifferentiation has not yet been described in association with clear cell chondrosarcoma.

Three patients are described who were initially diagnosed as having clear cell chondrosarcoma of the femur. Two were treated with en bloc resection for a clear cell chondrosarcoma. One of these had an undifferentiated sarcoma in a local recurrence after 6 years. In the second, metastasis of the clear cell chondrosarcoma developed 5½ years after surgery; autopsy revealed undifferentiated sarcoma in the lung, heart, and lumbar spine. The third patient had dedifferentiated clear cell chondrosarcoma at the time of resection following the biopsy diagnosis of clear cell chondrosarcoma. All three died with metastatic disease.

These three patients represent three different manifestations of dedifferentiation—at initial diagnosis, at recurrence, and at metastasis. To our knowledge, this is the first description of dedifferentiation occurring in clear cell chondrosarcoma.


Dedifferentiated chondrosarcoma with a noncartilaginous component mimicking a conventional giant cell tumor of bone.

Estrada EG, Ayala AG, Valerie L, Czerniak B.

Department of Pathology, Instituto Nacional de Ortopedia, Mexico City, Mexico; and the Departments of Pathology and Orthopedic Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX.

Ann Diagn Pathol 2002 Jun;6(3):159-63 Abstract quote

We report a case of dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor shows a close histologic resemblance to a conventional giant cell tumor of bone.

The tumor affected a 30-year-old woman with a long history of left shoulder discomfort and limitation of motion. Radiographic studies revealed a biphasic destructive lesion in the left proximal humerus composed of high-signal lobulated component on T2-weighted magnetic resonance image accompanied by a low signal intensity component exhibiting destructive growth with extension into soft tissue.

Microscopically, two different areas consisting of the chondroid tissue and nonchondroid giant cell-rich lesion resembling conventional giant cell tumor of bone were found. Considering that the prognosis and survival associated with these two entities are very different, it is important to be aware of this variant of dedifferentiated chondrosarcoma to avoid the misdiagnosis of conventional giant cell tumor of bone.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION
M6M6  
Minichromosome Maintenance Protein (MCM6) in Low-Grade Chondrosarcoma
Distinction From Enchondroma and Identification of Progressive Tumors

Andreas Helfenstein, MD,etal.
Am J Clin Pathol 2004;122:912-918 Abstract quote

The distinction between chondrosarcoma and enchondroma is difficult, and no reliable immunohistochemical or molecular methods are available. Differentiation is important because the therapeutic consequences range from radiologic follow-up to radical operation.

We studied 17 chondrosarcomas (12 grade 1) and compared them with 14 enchondromas immunohistochemically by using the monoclonal antibodies Ki-MCM6 (minichromosome maintenance protein 6), Ki-S5 (Ki-67), and Ki-S2 (repp86), in addition to the established clinical criteria.

In comparison with the other markers, Ki-MCM6 proved more effective at identifying proliferative activity in grade 1 chondrosarcomas. The MCM6 labeling index correlated with tumor grade and was significantly increased in grade 1 chondrosarcomas compared with enchondromas. The 5 cases of progressive chondrosarcoma also had a significantly higher MCM6 labeling index than the nonprogressive cases.

Furthermore, by means of the MCM6 labeling index, many cases of progressive disease were recognized among those of uncertain malignant potential, justifying their classification as low-grade chondrosarcomas.
S-100 positive  
Sox9  


Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors.

Wehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B.

Departments of Pathology and Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 085, Houston, TX 77030.

 

Hum Pathol 2003 Mar;34(3):263-9 Abstract quote

Over the last decade, a number of "master regulator" genes that control distinct pathways of mesenchymal differentiation have been discovered. These genes are expressed early during embryogenesis and initiate a cascade of gene expression responsible for specific cell lineage commitment.

Thus, identification of their products may allow the classification of seemingly primitive, morphologically uncommitted tumors such as small blue round cell tumors. The transcription factor Sox9 has been demonstrated to be a master regulator of the differentiation of mesenchymal cells into chondrocytes.

For this reason, we examined the utility of Sox9 in distinguishing mesenchymal chondrosarcoma (a small cell malignancy thought to be derived from primitive chondroprogenitor cells) from other primitive small cell malignancies. Representative sections from 90 cases of small blue round cell tumors (22 mesenchymal chodrosarcoma, 10 neuroblastomas, 11 rhabdomyosarcomas, 9 Ewing's sarcomas/primitive neuroectodermal tumors, 5 desmoplastic small round cell tumors, 7 small cell carcinomas, 6 Merkel cell carcinomas, 6 small cell osteosarcomas, 7 diffuse large B-cell lymphomas, 7 lymphoblastic leukemias/lymphomas, and 5 extraskeletal myxoid chondrosarcomas) were immunohistochemically stained with antibodies to Sox9 protein.

All but 1 mesenchymal chondrosarcoma showed positive nuclear staining in both primitive mesenchymal and cartilaginous components of the tumor. All other types of small blue round cell tumors, as well as the lymphomas and leukemias, were negative for Sox9 protein.

These findings confirm that mesenchymal chondrosarcoma has phenotypic features corresponding to the early condensational phase of cartilaginous differentiation. More important, Sox9 may serve as a useful tool in the differentiation of small cell malignancies.

TYPE II COLLAGEN  
Type II collagen as specific marker for mesenchymal chondrosarcomas compared to other small cell sarcomas of the skeleton.

Muller S, Soder S, Oliveira AM, Inwards CY, Aigner T.

1Department of Pathology, University of Erlangen-Nurnberg, Erlangen, Germany.

Mod Pathol. 2005 Aug;18(8):1088-94. Abstract quote  

Mesenchymal chondrosarcoma is a rare, usually highly malignant chondrogenic neoplasm. The diagnosis of mesenchymal chondrosarcoma can be challenging, it nonetheless has important therapeutic and diagnostic implications. Thus, biopsies of mesenchymal chondrosarcomas without conspicuous cartilaginous differentiation cannot be safely distinguished from other small cell mesenchymal neoplasms such as Ewing's sarcoma and peripheral neuroendrocrine tumors, synovial sarcomas and hemangiopericytomas, because all of these neoplasms might show overlapping histological features, and so far, there have been no safe immunohistochemical markers available in order to differentiate these neoplasms.

In our study on a large series of mesenchymal chondrosarcomas (n=30) and other small cell sarcomas (Ewing's sarcomas (n=12), synovial sarcomas (n=6), hemangiopericytomas (n=5), small cell osteosarcomas (n=3), and desmoplastic small round cell tumors (n=1)), we could establish the presence of type II collagen in the extracellular tumor matrix of the small cell areas of mesenchymal chondrosarcomas as a specific and sensitive marker to identify mesenchymal chondrosarcomas and to exclude other small cell neoplasms (except chondroblastic areas in small cell osteosarcomas). In contrast, the S-100 protein was less sensitive and vimentin and total collagen content unspecific for discriminating these neoplasms.

Thus, the presence of type II collagen in the extracellular tumor matrix significantly facilitates the diagnosis of mesenchymal chondrosarcomas in the absence of histologically visible chondroid matrix formation

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Enchondroma  
Chondroblastic osteosarcoma  

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS

Depends upon stage and histologic grade

If unresectable, especially tumors of the pelvis, location may play an important role
Distal extremities-good prognosis
Pelvis or shoulder girdle-guarded prognosis

If the tumor is completely resectable, prognosis depends mainly upon the grade

Grade I
Uncommon to metastasize
Grade II
10-33% metastasize
Grade III
70% metastasize
Survival  
Peripheral
>80% who die of the disease, do so after 5 years after diagnosis
Juxtacortical
Low rate of recurrence or mets
Mesenchymal
70% mortality secondary to distant mets or uncontrollable local growth
Clear cell
15% die with metastasis between 2-12 years after initial presentation
Dedifferentiated

90% die with distant mets within 2 years and most die within 1 year
Mets consist of noncartilaginous component

Most commonly mets to lungs, bones, and visceral organs

Recurrence

Curettage associated with 90% recurrence

Local recurrences or metastases usually occur within first 5 years of diagnosis

Rate of 27-35% regardless of tumor grade

Metastasis

Usually spreads within the medullary cavity
Pelvic tumors may invade the adjacent organs

Distant mets to lung, followed by skin and soft tissue
Mets to brain, liver, and bone are rare

Platelet-Derived Growth Factor- Receptor Expression Supports the Growth of Conventional Chondrosarcoma and Is Associated With Adverse Outcome

Irene Sulzbacher, M.D. ; Peter Birner, M.D. ; Klemens Trieb, M.D. ; Michaela Mühlbauer, M.D. ; Susanna Lang, M.D. ; Andreas Chott, M.D.

From the Departments of Clinical Pathology (I.S., P.B., S.L., A.C.) and Orthopedics (K.T.), University of Vienna Medical School, and the Orthopedic Clinic Gersthof (M.M.), Vienna, Austria.

Am J Surg Pathol 2001;25:1520-1527 Abstract quote

Bone cells are important targets of platelet-derived growth factors (PDGFs) because they stimulate proliferation of osteoblasts and chondrocytes.

In this study we wanted to determine the expression of PDGF-AA and PDGF- receptor in conventional chondrosarcomas and to compare the results with those obtained from benign enchondromas and non-neoplastic cartilage tissue. Sixty-seven chondrosarcomas, 20 enchondromas, and 5 specimens of healthy cartilage as well as 7 specimens of hypertrophic callus cartilage were immunohistochemically analyzed for the expression of PDGF-AA and PDGF- receptor, respectively. Additionally, the proliferation activity was examined with the MIB-1 antibody. Clinical follow-up data were available from 53 patients. A significant overexpression of receptor and factor was found in chondrosarcomas as compared with enchondromas (PDGF-AA p = 0.013, PDGF- receptor p <0.001). MIB-1 values were significantly higher in chondrosarcomas (p <0.001). In healthy joint cartilage no staining was detectable, whereas reactive cartilage of callus formation showed high expression levels. PDGF- receptor expression was significantly higher in grade 3 chondrosarcomas compared with grade 2 (p = 0.022) and grade 1 tumors (p = 0.002).

Survival analysis documented a significantly shorter overall survival for patients with high PDGF- receptor expression (p = 0.0172, log-rank test). Because PDGF- receptor expression positively correlates with the aggressiveness of chondrosarcoma, it may be considered as a possible target for novel therapeutic strategies.

CYCLOOXYGENASE-2 OVEREXPRESSION  
Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas.

Endo M, Matsumura T, Yamaguchi T, Yamaguchi U, Morimoto Y, Nakatani F, Kawai A, Chuman H, Beppu Y, Shimoda T, Hasegawa T.

Division of Orthopaedic Oncology, National Cancer Centre Hospital, Tokyo, Japan.


Hum Pathol. 2006 Apr;37(4):471-6. Epub 2006 Feb 3. Abstract quote  

Recent studies have shown increased levels of cyclooxygenase (COX)-2 in various human malignancies, including some bone and soft tissue tumors, but little is known about the presence of COX-2 in chondrosarcomas.

We performed immunohistochemical staining for COX-2 in 74 chondrosarcomas and compared the staining results with the characteristics and outcome of the patients. Thirty-seven men and 37 women between the ages of 14 and 81 years (median, 50 years) participated in the study. The tumors were located in the axial skeleton in 47 cases and in the long bones in 27 cases. The largest diameters of the tumors ranged from 2.7 to 32 cm (median, 8.0 cm).

The immunohistochemistry findings revealed the overexpression of COX-2 in 16 (22%) of the 74 patients. Thirteen (41%) of 32 grade 2 and 2 (67%) of 3 grade 3 chondrosarcomas showed overexpression for COX-2, whereas only 1 (3%) of 39 grade 1 chondrosarcomas showed overexpression.

Overexpression of COX-2 was significantly associated with histologic grade (P < .001) and a decreased disease-specific survival (P < .001). These findings suggest that COX-2 overexpression in chondrosarcoma is a negative prognostic factor that may be strongly associated with histologic grade.
TREATMENT En bloc excision preferred therapy

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Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


Commonly Used Terms

Bone and Joint Tumors

Extraskeletal Chondrosarcoma

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Last Updated November 6, 2006

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