References for this Review were identified by searches of Medline, GoogleScholar, and PubMed for references from relevant articles using the search terms “chordoma”, “brachyury”, and “proton radiation”. Only articles published in English between 1970 and October, 2011, were included.
ReviewChordoma: current concepts, management, and future directions
Section snippets
Historical overview and epidemiology
Chordoma is a rare cancer that accounts for 1–4% of all bone malignancies.1 Although histologically considered to be a low-grade neoplasm, chordomas are highly recurrent, making their clinical progression very similar to that of malignant tumours.2, 3 Population-based studies using the Surveillance, Epidemiology, and End Results (SEER) database suggest an incidence of chordoma of 0·08 per 100 000, with predominance in men and peak incidence between 50–60 years of age.4 Chordomas have very low
Pathogenesis
Chordomas were first characterised microscopically by Virchow in 1857.7 He described unique, intracellular, bubble-like vacuoles that he referred to as physaliferous, a term now synonymous with their histopathology. These physaliferous features of chordoma remain a distinguishing, if not pathognomonic, feature. Virchow hypothesised that chordomas were derived from cartilage; however, more contemporary evidence suggests that they are derived from undifferentiated notochordal remnants that reside
Clinical presentation
Chordomas are indolent and slow growing, therefore they are often clinically silent until the late stages of disease. The clinical manifestations vary and depend on location. Skull-base chordomas often grow in the clivus and present with cranial-nerve palsies. Depending on their size and involvement of the sella, endocrinopathy can also occur.18 Other rare presentations include epistaxis and intracranial haemorrhage.19, 20 Chordomas of the mobile spine and sacrum can present with localised deep
Diagnosis and molecular characteristics
Accurate diagnosis of tumours of the spine and skull base is of valuable prognostic significance. Chordomas and chondrosarcomas represent two biologically distinct categories of mesenchymal neoplasms that share morphological similarity and often present in similar locations throughout the neuroaxis; however, they differ in response to treatment.32 Advances in diagnostically differentiating between these two diseases have provided considerable insight into the surgical and postsurgical
Chordomas of the mobile spine and sacrum
In the 1970s, Stener and Gunterberg39 first introduced the idea of wide en-bloc surgical resection for the treatment of sacral tumours. Since then, en-bloc excision has remained a central tenant in the surgical management of sacral chordoma. With the advent of more aggressive surgery and wider surgical margins, local control of disease recurrence has substantially improved for chordomas of the sacrum,40 spine,41 and skull base.42
Early findings linked local recurrence to violations of tumour
Radiation therapy
Despite major advances in surgical interventions, total en-bloc resection is attainable in roughly 50% of sacral chordomas, with much lower rates for chordomas of the spine and skull base; therefore, recurrence is common without en-bloc resection.25, 42, 43, 51 The use of radiotherapy as primary or adjuvant treatment for chordoma is debated. Unfortunately, stand-alone radiotherapy has proven to be ineffective when coupled with debulking or palliative therapy.24
Advances in radiation technology
Retreatment
Despite best efforts at initial treatment, most chordomas will recur or progress. There are very few reports of treatment protocols and outcomes for recurrent lesions. Different treatment regimens have been described for recurrent disease, including re-irradiation79 and reoperation.80, 81, 82 Toxicities often limit the ability to safely deliver an effective radiation dose to a previously radiated field, and the dose delivered depends highly on lesion location, volume, and patient age and
Medical treatment
Anthracycline, cisplatin, alkylating agents,84 and camptothecin analogues85 have been reported to affect chordomas, and some case reports have suggested sensitivity of one of the histological variants—dedifferentiated chordoma.86 Unfortunately, systematic review of the literature found chordomas to be insensitive to conventional chemotherapies.30, 31
Molecular profiling of chordomas has revealed that they overexpress platelet-derived growth factor receptor (PDGFR)B, PDGFRA, and KIT receptors,
Current research and future directions
Despite aggressive surgical measures and high-dose radiation, local recurrence of chordoma is the marker of treatment failure.96 Studies have identified a common gene duplication of the transcriptional regulator, brachyury, in patients with familial and sporadic chordoma.15 Furthermore, tyrosine kinases and transcriptional regulators have been shown to be overexpressed in chordoma. Studies targeting these kinase domains and their downstream effectors could provide translational therapies and
Search strategy and selection criteria
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Classic chordoma coexisting with benign notochordal cell rest demonstrating different immunohistological expression patterns of brachyury and galectin-3
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Brachyury, SOX-9, and podoplanin, new markers in the skull base chordoma vs chondrosarcoma differential: a tissue microarray-based comparative analysis
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Chordoma: an immunohistologic study
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Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases
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Charged particle irradiation of chordoma and chondrosarcoma of the base of skull and cervical spine: the Lawrence Berkeley Laboratory experience
Int J Radiat Oncol Biol Phys
(1988)
Clinical outcome of sacral chordoma with carbon ion radiotherapy compared with surgery
Int J Radiat Oncol Biol Phys
Spinal cord tolerance to high-dose fractionated 3D conformal proton-photon irradiation as evaluated by equivalent uniform dose and dose volume histogram analysis
Int J Radiat Oncol Biol Phys
Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma
Int J Radiat Oncol Biol Phys
Sacral chordomas: impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor
Int J Radiat Oncol Biol Phys
Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No
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Response to imatinib plus sirolimus in advanced chordoma
Ann Oncol
Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse
Int J Radiat Oncol Biol Phys
Chordoma: a critical review of diagnosis and treatment
Orthop Clin North Am
Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients
Cancer
Chordoma and chondrosarcoma gene profile: implications for immunotherapy
Cancer Immunol Immunother
Chordoma: incidence and survival patterns in the United States, 1973–1995
Cancer Causes Control
Cranial chordomas in children and young adults
J Neurosurg
Lumbosacral chordoma: prognostic factors and treatment
Spine
Untersuchungen ueber die Entwicklung des Schaedelgrundes
In vitro characteristics of a sacrococcygeal chordoma maintained in tissue and organ culture systems
Acta Neuropathol
Uber die Ecchondosis physaliphora sphenooccipitalis
Centralbl Allg Pathol Anat
Three-dimensional reconstruction of human embryonic notochords: clue to the pathogenesis of chordoma
J Pathol
The pathology of the human notochord
J Pathol
Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas
J Pathol
Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation
Dev Dyn
T (brachyury) gene duplication confers major susceptibility to familial chordoma
Nat Genet
A molecular map of mesenchymal tumors
Genome Biol
The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells
J Clin Invest
Images in clinical medicine. Chondroid clival chordoma
N Engl J Med
Clival chordoma manifesting as nasal bleeding: a case report
Neuroradiology
Clival chordoma presenting with acute brain stem hemorrhage
Can J Neurol Sci
Clinicopathologic study of sacrococcygeal chordoma
Cancer
Sacrococcygeal chordoma: report of a case and review of the literature
Surgery
Current management of sacral chordoma
Neurosurg Focus
Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases
Spine
Chordoma of the mobile spine. A clinicopathologic analysis of 40 patients
Cancer
Imaging findings in tumors of the sacrum
AJR Am J Roentgenol
Primary tumors of the sacrum: diagnostic imaging
AJR Am J Roentgenol
Scintigraphic features of primary sacral tumors
J Nucl Med
Chordoma: a clinicopathologic study of metastasis
Am J Clin Pathol
Sacral chordoma: 40-year experience at a major cancer center
Neurosurgery
Chordoma: natural history and treatment results in 33 cases
J Surg Oncol
Surgical seeding of chordomas
Neurosurg Focus
Chordoma: the nonsarcoma primary bone tumor
Oncologist
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