Elsevier

The Lancet Oncology

Volume 13, Issue 2, February 2012, Pages e69-e76
The Lancet Oncology

Review
Chordoma: current concepts, management, and future directions

https://doi.org/10.1016/S1470-2045(11)70337-0Get rights and content

Summary

Chordoma is a rare bone cancer that is aggressive, locally invasive, and has a poor prognosis. Chordomas are thought to arise from transformed remnants of notochord and have a predilection for the axial skeleton, with the most common sites being the sacrum, skull base, and spine. The gold standard treatment for chordomas of the mobile spine and sacrum is en-bloc excision with wide margins and postoperative external-beam radiation therapy. Treatment of clival chordomas is unique from other locations with an enhanced emphasis on preservation of neurological function, typified by a general paradigm of maximally safe cytoreductive surgery and advanced radiation delivery techniques. In this Review, we highlight current standards in diagnosis, clinical management, and molecular characterisation of chordomas, and discuss current research.

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

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.

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