2002-03-01 Judith VMG Bovée Affiliation

1.Afdeling Pathologie, Leids Universitair Medisch Centrum, Postbus 9600, L1-Q, 2300 RC Leiden, the Netherlands

Summary

Figure 1: En bloc resection specimen of the proximal fibula of a 43 year old female, containing a lobulated bluish white, translucent tumour (4.5 x 2 x 1.9 cm) located centrally within the medullary cavity, consistent with central chondrosarcoma
Figure 2: Corresponding macro-slice showing a lobular architecture, and endosteal cortical thinning. Cytonucle ar appearance can be more readily appreciated in figure 3

Classification

Note

approximately 90% of chondrosarcomas are histologically of the conventional type; in addition to conventional chondrosarcoma, some rare variants with distinctive microscopic and clinical features are discerned: clear cell chondrosarcoma (1%), mesenchymal chondrosarcoma (2%), juxtacortical chondrosarcoma (2%) and extra-skeletal myxoid chondrosarcoma (5%). Furthermore, dedifferentiated chondrosarcoma is a relatively rare high grade sarcoma next to a low-grade conventional malignant cartilage-forming tumor, comprising 6-10% of all chondrosarcomas. Conventional chondrosarcomas can be categorized according to their location in bone. The majority of chondrosarcomas (75%) are located centrally within the medullary cavity (central chondrosarcoma), a small percentage of which arise within a preexisting benign precursor (enchondroma). While most enchondromas are solitary, patients with Olliers disease and Maffuccis syndrome demonstrate multiple enchondromas.A minority (15%) of chondrosarcomas develops from the surface of bone (peripheral chondrosarcoma) as a result of malignant transformation within the cartilaginous cap of a solitary or hereditary pre-existent osteochondroma.

Clinics and Pathology

Epidemiology

primary malignant bone tumours occur 1/100,000, of which 17-24% consists of chondrosarcoma; the majority of patients are between 35 and 60 years old with equal sex distribution

Clinics

compared to benign cartilaginous tumours, chondrosarcomas more frequently present with pain and tenderness; they usually develop in the trunk, pelvis and long bones.

Figure 3: Micrograph displaying low cellularity with limited cytonuclear atypia, and a high amount of chondroid matrix surrounding tumor cells consistent with a grade I chondrosarcoma. Note the presence of a binucleated cell

Pathology

There are no apparent cytonuclear differences between central and peripheral conventional chondrosarcomas and both are histologically classified into three grades using the criteria of Evans et al.

Grade I chondrosarcomas demonstrate low cellularity, limited cytonuclear atypia, few multinucleated cells, a mainly chondroid matrix and the absence of mitoses;

Grade II chondrosarcomas demonstrate increased cellularity, and increased muco-myxoid degeneration of the matrix. There is moderate cytonuclear atypia and occasional mitoses are found.

Grade III chondrosarcomas are highly cellular, with nuclear polymorphism, mitoses and a mostly myxoid matrix;

Increasing histological grade is correlated with higher metastatic potential; it is considered difficult to assess the histological grade of cartilaginous tumours and to reliably distinguish between benign tumours and those of low-grade malignancy.

Treatment

because chondrosarcoma is highly resistant to chemotherapy and radiotherapy, surgical treatment is the only option for curative treatment

Evolution

the majority of central chondrosarcomas are considered to arise de novo and malignant transformation of solitary enchondroma is extremely rare (

Prognosis

metastasis in chondrosarcoma highly depends on the histological grade of malignancy; grade I chondrosarcomas demonstrate local recurrence, but seldom metastasize; grade II chondrosarcomas demonstrate metastases in 10-30% of the cases, whereas grade III chondrosarcomas demonstrate metasases in the majority of cases. In contrast to chondrosarcomas located elsewhere in the skeleton, those located in the phalanx behave as a locally aggressive lesion with minimal metastatic potential

Cytogenetics

Cytogenetics morphological

extra-skeletal myxoid chondrosarcoma, is characterized by a reciprocal translocation t(9;22)(q22;q12), fusing the EWS to the CHN gene.

cytogenetic analysis on a heterogeneous group of chondrosarcomas revealed that structural aberrations of chromosomes 1, 6, 9, 12 and 15 and numerical aberrations of chromosomes 5, 7, 8 and 18 were most frequent; abnormalities of chromosome 1 and 7 (especially trisomy 7) were confined to malignant cartilaginous tumours; like in other mesenchymal neoplasms, band 12q13-15 is prominently involved in the aberrations;

Aberrations of chromosome 9, especially the 9p12-22 region are more common in central chondrosarcomas.

the presence of chromosome aberrations was found to strongly correlate with increasing histological grade; complex aberrations were mainly seen in the high-grade chondrosarcomas.

Loss of 13q was found to be an independent factor for metastasis, regardless of tumor grade or size.

Additional anomalies

in a comparative study of central and peripheral chondrosarcomas, 19 of 20 peripheral chondrosarcomas showed LOH at all loci (EXT, EXTL, 13q14, 17p13, 9p21 and chromosome 10) tested while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14 and 17p13. DNA-flow-cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA-indices 0.56 - 2.01), whereas central chondrosarcomas were predominantly peridiploid; these results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative; no somatic mutations in the EXT1and EXT2 genes were found in secondary peripheral chondrosarcoma.

A mutation (R150C) in the PTH/PTHrP type I receptor was demonstrated in 2 patients with Olliers disease (one germline and one somatic), while this mutation was absent in 50 sporadic chondrosarcoma specimens.

unfortunately, most other genetic analyses on chondrosarcoma were performed on a heterogeneous group including all different subtypes of chondrosarcoma; ploidy-analysis of chondrosarcomas has been described and aneuploidy is more frequently found in high-grade chondrosarcomas; two series of chondrosarcomas (n=23 and n=50) studied by CGH revealed extensive genetic aberrations; the majority of these changes were gains of whole chromosomes or whole chromosome arms, most frequent at 20q (32-38%), 20p (24-31%), and 14q23-qter (24-28%). A correlation between gain at 8q24.1 and shorter overall survival was reported; amplification of the c-myc proto-oncogene, located at 8q24, was found in four of 12 chondrosarcomas, and was not associated with any clinicopathological features. The only recurrent high-level amplification, seen in two tumours (7%), affected the minimal common region 12cen-q15; although both cytogenetic analysis and CGH point at 12cen-q15, CDK4, MDM2 and SAS were not frequently amplified in chondrosarcoma.

Partial allelotypings of a heterogeneous group of chondrosarcoma revealed that in addition to LOH at the EXT-loci on chromosomes 8 (4/17) and 11 (7/17), LOH was found at 10q11 (12/18), the Rb- (9/25) and p53-locus (7/28). Overexpression of the p53 protein, 17p1 alterations and TP53 mutations have been observed mainly in high-grade chondrosarcomas, suggesting that the p53 gene could play a role in the progression of chondrosarcoma.

Dedifferentiated chondrosarcoma: investigating both the cartilaginous as well as the high-grade malignant component of dedifferentiated chondrosarcoma, an identical somatic 6 bp deletion in exon 7 of p53 and loss of the same copy of chromosome 13 provided compelling evidence for a common origin instead of the "collision tumor_ theory; in addition, many different genetic alterations were found, indicating that the separation of the two clones is a relatively early event in the histogenesis of dedifferentiated chondrosarcoma.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
8101872	1993	Amplification of c-myc oncogene and absence of c-Ha-ras point mutation in human bone sarcoma.	Barrios C et al
11763313	2001	Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes.	Bovée JV et al
8402563	1993	Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions.	Bridge JA et al
9060841	1997	Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma.	Brody RI et al
1342971	1992	Amplification of the c-myc proto-oncogene in human chondrosarcoma.	Castresana JS et al
7774891	1995	p53 expression and DNA ploidy of cartilage lesions.	Coughlan B et al
498016	1979	Cytophotometric studies of the nuclear DNA content in cartilaginous tumors.	Cuvelier CA et al
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7726168	1995	Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8.	Hecht JT et al
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11850620	2002	A mutant PTH/PTHrP type I receptor in enchondromatosis.	Hopyan S et al
6580940	1984	Flow DNA analysis of primary bone tumors. Relationship between cellular DNA content and histopathologic classification.	Kreicbergs A et al
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11793445	2002	Cytogenetic aberrations and their prognostic impact in chondrosarcoma.	Mandahl N et al
9840532	1998	Altered p53 is associated with aggressive behavior of chondrosarcoma: a long term follow-up study.	Oshiro Y et al
8818661	1996	Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas.	Raskind WH et al
8625095	1995	p53 expression in dedifferentiated chondrosarcoma.	Simms WW et al
11793371	2002	Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group.	Tallini G et al
8260365	1993	p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas.	Wadayama B et al
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Citation

Judith VMG Bovée

Atlas Genet Cytogenet Oncol Haematol. 2002-03-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5063/chondrosarcid5063

Historical Card

2000-01-01 Bone: Chondrosarcoma by Judith VMG Bovée Affiliation