Update on the Cytogenetics and Molecular Genetics of Chordoma
© The Author(s) 2004
Received: 25 January 2005
Accepted: 7 February 2005
Published: 15 February 2005
Chordoma is a rare mesenchymal tumour of complex biology for which only histologic and immunohistochemical criteria have been defined, but no biomarkers predicting the clinical outcome and response to treatment have yet been recognised. We herein review the interdisciplinary information achieved by epidemiologists, neurosurgeons and basic scientists on chordoma, usually a sporadic tumour, which also includes a small fraction of familial cases. Main focus is on the current knowledge of the genetic alterations which might pinpoint candidate genes and molecular mechanisms shared by sporadic and familiar chordomas. Due to the scarcity of the investigated tumour specimens and the multiple chromosome abnormalities found in tumours with aberrant karyotypes, conventional cytogenetics and Fluorescence In Situ Hybridization failed to detect recurrent chordoma-specific chromosomal rearrangements. Genome-wide approaches such as Comparative Genomic Hybridization (CGH) are yet at an initial stage of application and should be implemented using BAC arrays either genome-wide or targeting selected genomic regions, disclosed by Loss of Heterozygosity (LOH) studies. An LOH region was shown by a systematic study on a consistent number of chordomas to encompass 1p36, a genomic interval where a candidate gene was suggested to reside. Despite the rarity of multiplex families with chordoma impaired linkage studies, a chordoma locus could be mapped to chromosome 7q33 by positive lod score in three independent families. The role in chordomagenesis of the Tuberous Sclerosis Complex (TSC) genes has been proved, but the extent of involvement of TSC1 and TSC2 oncosuppressors in chordoma remains to be assessed. In spite of the scarce knowledge on the genetics and molecular biology of chordoma, recent initiation of clinical trials using molecular-targeted therapy, should validate new molecular targets and predict the efficacy of a given therapy. Comparative genetic and biomolecular studies should enhance the molecular taxonomy of chordoma which might have a prognostic significance and better orient the therapeutic options.
Chordomas are rare, low-to-intermediate grade malignant tumours which occur along the length of the craniospinal axis. They are attributed to neoplastic transformation of embryonic remnants of the primitive notochord . Incidence is around 0.05/100,000/year . They account for <1% of the central nervous system tumours  and <5% of all primary malignant bone tumours . The most common locations are the sacrococcygeal region (45-49%), the base of the skull (36-39%), and the spinal axis (8-15%) . In the cranio-cervical region seven points of origin have been indicated: dorsum sellae, Blumenbach's clivus, retropharyngeal notochord vestiges, remnants in the apical ligament of the dens, nuclei pulposi of the cervical vertebrae, vestiges in the squama occipitalis, and ectopic localizations . Nose and paranasal sinuses primitive chordoma have been suggested not to be real ectopic localizations as more properly chordoma arose from remnants .
No racial predilection for chordomas has been reported, male-to-female ratio is generally 2: 1 [3, 8]. Every age can be involved with predominance for the third and fourth decades for intracranial localization, while spinal chordomas are generally observed at older ages because of late signs and symptoms [3, 8]. Chordoma has no known association with irradiation or any other environmental factors. A small percentage of cases have a familial pattern of inheritance [9–13].
Clinical presentation, therapy and prognosis
Chordomas develop in the bone, so they initially grow extradurally with bone destruction and secondary extension into adjacent soft tissues ; they have common characteristics of a malignant tumour, with local invasiveness, tendency for recurrence, and the potential to metastasize. Distant metastases of chordomas have been described with prevalence up to 43% ; almost all cases were observed in sacrococcygeal localizations; the low rate of systemic spread for skull base neoplasms, which ranges from 0% to 10%, is probably related to the fact that the patients die of the local effect of their tumours before metastases develop [16, 17].
Clinically they are slow-growing tumours characterized by local spread. Symptoms manifest late, even after years, and therefore the local extent of disease is often huge at diagnosis. Pain and neurological symptoms from local compression are the main subjective complaints of the patient. They obviously depend on tumour location. Symptoms like (from the earliest to the latest) low back pain, anaesthesia and paraesthesia, intestinal obstruction, are caused by sacral chordoma. Symptoms and signs of compression of nerve roots and/or spinal chord are related to vertebral chordoma.
Headache and diplopia are the most common symptoms related to chordoma of the clivus and base of the skull .
The V cranial nerves are also frequently involved, due the progressive growth with invasion of other neighbouring structures such as the cavernous sinus. Signs and symptoms include also visual loss and limitation of visual field. Extraocular complaint can be dysphagia, dyspnea, dysphonia, facial pain, facial paresis, hearing loss, tinnitus, dizziness and ataxia, after brain stem compression. Anterior extension to the pharynx can explain pharyngolaryngeal and otological symptoms, whereas extension to nose and paranasal sinuses can cause nasal obstruction, ipo-anosmia, hyponasal speech, mucopurulent discharge, and, rarely, epistaxis [5, 8].
Distant metastases may occur late across the natural history of the disease, mainly to the lungs, but also to bone, liver, distant soft tissues and skin.
Given the natural history and histological characteristics of the disease, treatment is based on local modalities. Surgery is the treatment of choice. The aggressiveness of local resection has been correlated to the patient's outcome, in terms of both local control and survival. However, surgery is often confronted by major sequelae, which may follow adequate excision of several sacral presentation, with loss of urogenital and rectal function in case of bilateral section of S2, or below, nerve roots, as well as cranial nerves impairments after resection of clival chordomas.
Prognosis of chordomas is related to the extent of surgical removal: five-year survival of 35% is reported with incomplete resection also if followed by conventional radiation therapy . Better results are reported with aggressive surgical treatment and proton-beam postoperative radiotherapy with a disease-free survival rate from 50%  to 77% at 5 years  and from 45% to 69% at 10 years [19, 20].
If surgery is unfeasible, radiation therapy is the second choice in order for eradicative intent. Chordoma is a relative radioresistant tumour, with 60-70 Gy of photon radiation therapy needed for best responses. Progression-free survival rates in the 30% range have been reported with radiation therapy alone.
Chemotherapy has been resorted to, but only anecdotal reports of activity of chemotherapeutic agents or regimens are available. Drugs active in sarcomas, including Doxorubicin and Ifosfamide, as well as in carcinomas or other bone sarcomas, including Cisplatin and Etoposide, have been administered. However, chordomas are generally viewed as chemo-resistant, low-grade tumours, for which standard cytotoxic chemotherapy lacks an established role, even a palliative one, in advanced chordoma.
The prognosis of chordoma is affected by a variety of clinical and pathologic characteristics. Important features include tumour location, size and resectability, as well as the age and the gender of the patient; larger tumours, female gender, and age of over 40 years have been associated with a poorer outcome [16, 17, 23, 24].
Macroscopic/microscopic features and immunohistochemistry
Chordomas are of three overlapping and sometimes coexisting histopathologic types: conventional, chondroid and dedifferentiated. The chondroid chordoma, first described by Heffelfinger in 1973 , is characterized by a cartilaginous hyaline component and by a supposed better prognosis . Dedifferentiated or sarcomatoid chordomas are high-grade neoplasms, which account for only 5% of cases .
Differential diagnosis of chordomas includes primary bone tumours, cartilagineous neoplasms such as chondromas or chondrosarcomas, epithelial neoplasms such as mucinous-forming adenocarcinoma or salivary neoplasms, metastases, neurinoma, neurofibroma, meningioma, neuroblastoma, haemangioma and lymphoma.
S-100 positivity, often seen in chordomas (Fig. 1C), can differentiate from epithelial neoplasms [28, 29]. Cytokeratin antibodies and EMA (epithelial membrane antigen) positivity of chordoma (Figs. 1D and 1E) is used to distinguish it from cartilaginous neoplasms, where the absence of these epithelial markers should be the rule . Some chordomas stain positive with vimentin antisera (Fig. 1F), which reflects mesenchymal differentiation .
Chordoma is a disembryogenetic tumour attributed to malignant transformation of intraosseous persistent notochordal tissue . In agreement with this view are the close histological and immunohistochemical similarities with the embryonic notochord and the correlation of chordoma development to location and incidence of notochordal vestiges .
It is known that in chick embryo the notochord develops through four periods of activity which are related to cytodifferentiation and functional maturation, with cessation of mitosis, cell apoptosis and decrease in the nucleolar volume in the fourth period . It was also found by canine/bovine notochord cell cultures that a small number of notochordal cells persist in the nucleus pulposus with the function of maintaining disk integrity . In human, the notochord forms from ectodermal cells during the third gestational week , then inducing chondrification and segmentation of the mesenchymal elements of the vertebral bodies. It obliterates in the second gestational month, leaving behind microscopic foci of notochord tissue in the most cranial and caudal of vertebral bodies. During the involution process the notochord normally completely disappears from the vertebrae to eventually form the nucleus pulposus of the intervertebral disk which is progressively replaced by fibrocartilage from the surrounding tissue by the age of 1-3 years. Macroscopic notochordal remnants, termed ecchordosis physaliphora (EP) are found at the base of the skull in up to 2% of adult autopsies and have been considered as one of the precursor lesions of classic chordomas [32, 35]. It has been pointed out that classic vertebral chordomas occur in bone and do not develop in the notochordal vestiges of the intervertebral disks . In keeping with this prediction a few intraosseous benign notochordal cell tumours have been described [37, 38] and recently the first histologically confirmed case of a classic chordoma in the coccyx arising in a precursor benign notochordal lesion has been reported . Intraosseous counterparts at the base of the skull have been also documented in a large microscopic study on vertebral columns from atlas to coccyx and pieces of the clival portion of the skull base dissected from 100 autopsy cases: a surprisingly high incidence (26 in 20 cases) of intraosseous benign notochordal cell tumours with anatomical distribution and immunohistochemical reactivity identical to that of classic chordomas have been identified . The results showed that 11.5% of the clivus, 5.0% of the cervical vertebrae, 0% of the thoracic vertebrae, 2.0% of the lumbar vertebrae and 12% of the sacrococcygeal vertebrae were affected. These results support other evidence that classic chordomas develop from intraosseous benign notochordal cell tumours.
Families with multiple occurrence of chordoma
Foot et al, 1957
brother and sister
Enim et al, 1963
Kerr et al, 1975
3 in three generations
Chetty et al, 1991
1 with family history
Korczak et al, 1997
9 in three generations
Stepanek et al, 1998
4 in 2 generations
sacral, clival nasopharyngeal
20, 39, 28, 31
Dalprà et al, 1999
Miozzo et al, 2000
father and two daughters*
Kelley et al, 2001
two first cousins once removed°
The study performed by Kelley  in the family reported by Stepanek et al  consisted in a genomewide analysis for linkage which first yield a 2.2 lod score at marker D7S2195 on chromosome 7q, based on only the 10 affected family members. To increase the power of the linkage analysis and to narrow the candidate disease gene region, additional members of this large family were examined together with two small independent families, one with two affected cousins, once removed, and another representing a branch of a previously reported three-generation family . The combined analysis with 20 markers on 7q showed a maximum two-point lod score of 4.05 at marker D7S500. Multipoint analysis based only on the affected individuals and haplotyping of the three families members pinpointed a minimal disease region of 11.1 cM from D7S1804 to D7S684 consistent with mapping to 7q33 of a locus for familial chordoma. No LOH was found at any of the markers residing in the 7q critical region, precluding narrowing of the candidate region .
So far, 7q33 emerges as a strong candidate region for chordoma susceptibility based on the significant lod score obtained by the combined analysis of three families, one of which with a well suitable structure for linkage analysis. Conversely 1p36 is a proven LOH region in chordoma [11, 46], which might harbour a susceptibility gene, should the linkage be reassessed in the family with two members showing LOH in the tumours and/or in additional families. Both 7q33 and 1p36 regions are compatible with the suspected heterogeneity of susceptibility loci for chordoma. Evidence for this is also provided by the outcome of chordoma in the context of Tuberous Sclerosis (MIM#191100), an autosomal dominant syndrome, characterised among different clinical signs, by hamartomas in multiple organs, which is caused by germline mutations in either of two genes TSC1 (MIM 605284) and TSC2 (MIM 191092) which behave like tumour suppressors. TSC1 and TSC2 products, known as hamartin and tuberin, act as a heterodimer; thus the inactivation of either gene impairs the same pathway leading to the same clinical phenotype [49–51]. The association between chordoma and TSC has been highlighted by Lee-Jones et al  who datamined the literature for the unusual occurrence of chordoma in the context of tumour predisposition syndromes and identified three reports of chordomas in patients with Tuberous Sclerosis Complex (TSC) [52–54]. The same group demonstrated in two cases of sacrococcygeal chordomas developed by a newborn with germline TSC1 mutation and a 33-week aborted foetus with a germline TSC2 mutation, somatic inactivation of the corresponding wild type allele by LOH and immunohistochemistry . It should be noted that the early onset characterises also the three reported TSC-associated chordomas, which were discovered either during the first days of life  or in childhood [53, 54] consistent with genetic predisposition mediated via germline mutation in a TSC gene.
No other cases of chordomas found with any coexisting tumours in the context of cancer predisposition syndromes are known.
Genetic alterations in chordoma: cytogenetics, FISH and CGH
Genetic alterations in chordoma: LOH studies
The first LOH study on chordomas concerned the Rb locus (13q14) at which LOH was detected in two of 7 sphenooccipital/clivus tumours, and proposed by correlation with the clinical behaviour as a marker of aggressive tumours . The finding is consistent with the loss of chromosome 13 (most frequently occurring after chromosome 3) ascertained by cytogenetics and CGH [CGAP; ]. Further LOH studies evidenced the loss of 17p, 9p and 18q, where known oncosuppressor genes are mapped . It has been reported that the combined loss of p53 function and RB1 protein leads to genomic instability, a finding consistent with the model of progressive accumulation of genetic changes with increasing malignancy [68, 70].
A targeted study involved the 1p36.13 interval , which is comprised within the commonly deleted chromosome 1p in chordoma [10, 47, 58, 60]. The 1p36.13 band had been pinpointed by the recurrent breakpoints identified in two tumour recurrences of the founder of an Italian chordoma family  and the haplotype and LOH information retrieved on this family . Typing of 31 region-specific microsatellites evidenced LOH across 1p36.13 in 25 out of 27 sporadic chordomas which were tested , data confirmed by further analyses on a wider tumour panel (unpublished observations). A common deleted region, with a genetic length of 3.9 cM, was shared by 23 chordomas, raising the option of hunting candidate genes in this region. A few difficulties are represented by the consistent physical length (3 Mb) of this subtelomeric region, the high gene density and its common loss in a wide spectrum of solid tumours, mainly neurological [71, 72], suggesting a possible non-specific role in chordoma. The first selection of region-specific genes was based on genes with functions related to development or regression of the notochord such as Caspase 9 (CASP9) and Ephrin 2A (EPH2A). CASP9 is a ubiquitously expressed protease which triggers the apoptotic pathway by releasing cytochrome c from mitochondria into the cytosol . EPH2A is a tyrosine kinase receptor involved in tail notochord formation during mouse embryo development . The murine orthologue is regulated by members of the p53 gene family and plays an important role in apoptosis: it is found upregulated during angiogenesis in tumours . Additional candidate genes come to the attention when a wider LOH region, which is shared by a lower percentage (40%) of chordomas is considered. They include the paired box 7 (PAX7) gene encoding a transcriptional factor expressed in the neural tube which is regulated by notochord specific signals , the differentially screening-selected gene aberrant in neuroblastoma (DAN), involved in the negative regulation of cell proliferation , the Dishevelled 1 gene (DVL1), a key factor in Wnt signalling expressed in the neural tube  and a few genes belonging to the tumour necrosis factor receptor superfamily (TNFRSF-1B, -8, -9, -14), the DNA fragmentation factor (DFF-A and- B) and TP73 [UCSC], all acting in apoptotic pathways.
Preliminary data on RT-PCR expression analysis of eight chordomas evidenced the lack of CASP9, EPHA2 and DVL1 transcripts in 5, 1 and 4 tumours, respectively. Interestingly, some of the non-expressing tumours did not show 1p36 LOH suggesting a loss of function as a result of point mutation or other mechanisms . Because chordoma cells are unique, a control cell type of similar origin is difficult to identify; the nucleus pulposus is currently being used as suitable reference for expression studies.
No LOH has been detected in tumour specimens from the affected family members at 7q33, a region cosegregating with susceptibility to chordoma in the family described by Kelley et al . According to the authors, the absence of LOH may indicate that the disease gene exerts its oncogenic effect in a dominant way. No LOH at 7q33 was detected in the tumours from the affected members of the Italian family [unpublished observations].
As reported above, the somatic loss of the wild-type TSC1 and TSC2 allele was found in the chordomas developed by two patients with Tuberous Sclerosis, carrying germline mutations of either TSC gene . TSC1 and TSC2 are usually considered as a complex with one function. Genetic studies in mammalian systems  and Drosophila [80, 81] showed that the TSC1/TSC2 complex inhibits cell growth in both mass or size and cellular proliferation thus exerting a positive control of apoptosis [82, 83]. It would be worthwhile monitoring LOH at both TSC genes in a significant sample of chordomas, especially sacrococcygeal chordomas which are ascertained in children  and might be on a hereditary basis, and proceed with the mutation screening in the LOH-positive cases. The TSC genes, whose pathogenetic role in chordoma development has been disclosed, may provide through their impaired function a link to other susceptibility genes, yet to be detected.
Molecular markers in relationship to clinical parameters
There is still a deep gap in our understanding of the genetic basis and molecular biology of chordoma. Two studies have examined the role of molecular markers in chordoma in relationship to clinical parameters [56, 69], but currently they have only an exploratory meaning, which cannot lead to advance the care and management of this cancer.
The first study showed that chordoma cells from five patients had an increased telomere length compared with leukocytes from age-matched controls, in marked contrast to telomere length reduction which is observed in most cancers. Telomerase activity was present in chordoma cells from one of the two patients who were studied, but to a lesser degree compared with Hela . The second study showed that chordomas can be added to the list of malignancies demonstrating microsatellite instability (MIM) which was evidenced in six out of 12 tumours tested, but pointed out that LOH may prove to portend a worse prognosis than MIN .
Chordoma is unique among mesenchymal tumours in the epithelioid features seen. Immunoreactivity for cytokeratins (Fig. 1D), epithelial membrane antigen (Fig. 1E), S-100 protein (Fig. 1C), vimentin (Fig. 1F) and neurofilaments helps diagnosis and discrimination from other mucin-producing bone cancers, but does not represent a prognostic feature. The complex immunophenotype of chordoma has been related to its origin from notochord, which undergoes conspicuous changes in location and morphology during embryonic development . Detailed analyses were thus conducted on chordoma and foetal notochord aiming at studying the expression of each component of cytokeratin . Cytokeratins CK8 and CK9 were found to be shared by both chordoma and notochord, as well as galectin-3, an endogenous carbohydrate-binding protein . Recently galectin-3 has been demonstrated to be an immunohistochemical marker most useful to distinguish the pathologically overlapping entities of chordomas and myxoid chondrosarcoma .
The expression of cell adhesion molecules (CAMs) including E-cadherin, alpha-catenin, beta-catenin, gamma-catenin and neural cell adhesion molecule (NCAM) has been associated with formation and maintenance of chordoma tissue architecture and found of diagnostic value for discriminating chordoma from chondrosarcoma, along with the cytokeratins [89, 90]. However no significant correlation was found between the decreased expression of CAMs, observed in most chordomas and the histological grade of malignancy, cellular growth pattern or clinical parameters. Further studies tested the hypothesis that the expression of certain growth factors and/or structural proteins might be correlated with the biological behaviour of chordomas. Investigations on steroid hormone receptors, which are involved in tumour growth, evidenced that progesterone receptor B and oestrogen receptor alpha were expressed in chordoma and hence associated with tumour progression . High levels of transforming growth factor alpha and basic fibroblast growth factor expression were linked to higher rates of recurrence and strong fibronectin expression was also associated with poor prognosis, being thus considered an additional marker of aggressiveness .
Conclusions and future directions
Chordoma is a peculiar tumour, which constitutes a nosological entity by its own. Due to its rare occurrence the tumour specimens which could be processed for conventional and FISH-based chromosomal analyses are yet scarce. When the karyotype was aberrant, a wide variety of both numerical and structural aberrations had been detailed, but no distinctive sequence of aneuploidy or common tumour-specific chromosome rearrangements could be identified. Only one study based on standard CGH analysis has been applied and revealed a good matching with the previous cytogenetic findings . Analysis of additional tumour specimens is warranted to select common regions of imbalance for more detailed studies using array-CGH by full coverage of specific BACs and targeted LOH. Positional candidate genes should thus emerge, besides those residing in genomic intervals, such as 1p36 and 7q33 which are thought to be relevant for chordoma genesis and/or progression and are currently under intense investigation. It is currently likely that a gene at 7q33 is involved in susceptibility to chordoma, according to the consistent linkage results obtained in 3 out of the 8 families with chordoma so far studied . The lack of LOH at 7q33 markers, if corroborated by further data, would classify the predisposition gene as an oncogene, consistent with the common gain of 7q detected by cytogenetics and molecular cytogenetics . It is also well proven that the 1p36 interval is preferentially lost in chordoma  and might thus harbour at least one oncosuppressor whose role in early or late stages of chordomagenesis should be pointed out. Whether or not germline mutation in this latter potential candidate might also sustain genetic susceptibility awaits confirmation. The role of TSC1 and TSC2 genes in congenital or early onset chordomas has been established . LOH test at both TSC genes should be a useful adjunct in chordomas to screen the positive cases for germline mutations allowing to establish the epidemiological contribution of these two cancer genes to chordoma onset. Position-independent candidate genes might also emerge by other approaches: the rationale behind it is their involvement in apoptotic pathways, as their constitutional or somatic deregulation might lead to defective notochord regression, i.e. the premise for subsequent neoplastic transformation. Once the pathogenesis of chordoma is elucidated, cytological markers of prognostic significance might be used in clinical practice. Therapeutic strategies could benefit from these discoveries. Recently imatinib mesylate (Gleevec, Novartis Pharma AG, Basel, Switzerland) , a highly selective inhibitor of the protein tyrosine kinase family that comprises Abl, the platelet-derived growth factor receptor (PDGF-R) α and β  and the product of the c-kit protooncogene, KIT, has been found to have anti-tumour activity in patients with advanced chordomas . All the six patients who were treated had tumours found positive for PDGFRβ which was shown to be phosphorylated in four of them. Further investigation on the role of PDGFRβ in chordomas should substantiate these findings, allowing to prospectively register all those patients who might benefit from imatinib mesylate treatment.
The authors thank all those who took part in this study. We would like to acknowledge the following: Prof. AM Fuhrman Conti and L. Dalprà (University of Milano Bicocca), Dr M. Miozzo, Dr F. Orzan and Dr M. Longoni (University of Milan), Prof. C. Doglioni and Dr N. Boari (S. Raffaele Hospital, Milan). This work was partially supported by an AIRC (Associazione Italiana per la Ricerca sul Cancro) 2001-2003 grant to L.L.
The accession number and URLs for data in this article are as follows:
- Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nln.nih.gov/Omim/for chordoma (OMIM 215400), Tuberous Sclerosis (OMIM #191100), TSC1 (OMIM 605284) and TSC2 (OMIM 191092),
- Mitelman database of chromosome aberrations in cancer. Updated May 2003, http://cgap.nci.nih.gov/chromosomes/Mitelman, Mitelman F, Johansson B, Mertens F, editors, recurrent Case for Diagnosis/chordoma,
- UCSC browser information,
http://www.genome.ucsc.edu, for TNFRSF-1B, -8, -9, -14, DFF-A and -B and TP73.
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