Chordoma

Presentation

Chordomas can arise from bone in the skull base and anywhere along the spine. The two most common locations are cranially at the clivus and in the sacrum at the bottom of the spine. Very rarely, chordomas present outside of the skull base or spine; these are called extra axial chordomas.

Genetics

A small number of families have been reported in which multiple relatives have been affected by chordoma. In four of these families, duplication of the brachyury gene was found to be responsible for causing chordoma.

A possible association with tuberous sclerosis complex (TSC1 or TSC2) has been suggested.

Mechanism

• mTOR signaling is hyperactive in sporadic sacral chordomas: in one study 10 out of 10 sacral chordomas exhibited phosphorylation of Ribosomal protein s6 and EIF4EBP1 by immunohistochemistry
• Partial or complete PTEN (gene) deficiency is observed in nearly all sacral chordomas
• In a study of 49 chordomas Akt, TSC2, and EIF4EBP1 were phosphorylated in 92%, 96% and 98% of cases, respectively.
• In a tissue microarray containing 21 chordomas Platelet-derived growth factor receptor-beta (PDGFR-b), epidermal growth factor receptor (EGFR), KIT (CD117) and HER2 were detected in 100%, 67%, 33% and 0% of cases, respectively.
• The CDKN2A (p16) and CDKN2B (p15) loci on chromosome 9p21 are frequently deleted in chordomas Another study found CDKN2A immunoreactivity in just 4% of cases.
• 62% of chordomas express the High Molecular Weight Melanoma Associated Antigen, also known as Chondroitin sulfate proteoglycan 4 (CSPG4) which has been the target of immune therapy.
• In 2009, scientists discovered that an inherited gene duplication is responsible for the familial form of this disorder. Familial chordoma are rare, with an estimated rate of 0.4% in all Chordomas.

Diagnosis

In 2015 the first consensus guidelines for the diagnosis and treatment of chordoma were published in The Lancet Oncology. These tumors express brachyury and cytokeratin, which can be detected by immunohistochemistry.

Classification

There are three histological variants of chordoma: conventional, chondroid and dedifferentiated.

• The histological appearance of classical chordoma is of a lobulated tumor composed of groups of cells separated by fibrous septa. The cells have small round nuclei and abundant vacuolated cytoplasm, sometimes described as "physaliferous" because of their cytoplasmic vacuoles, and their resemblance to the physalis plant.
• Chondroid chordomas histologically show features of both chordoma and chondrosarcoma.

Treatment

Consensus treatment guidelines have been developed to improve care quality and consistency. In 2015, an international panel published the first clinical practice guidelines for chordoma. In 2017, best practices were published for the treatment of recurrent chordoma.

In most cases, complete surgical resection followed by radiation therapy offers the best chance of long-term control. Incomplete resection of the primary tumor makes controlling the disease more difficult and increases the odds of recurrence. The decision whether complete or incomplete surgery should be performed primarily depends on the anatomical location of the tumor and its proximity to vital parts of the central nervous system.

Chordomas are relatively radioresistant, requiring high doses of radiation to be controlled. The proximity of chordomas to vital neurological structures such as the brain stem and nerves limits the dose of radiation that can safely be delivered. Therefore, highly focused radiation such as proton therapy and carbon ion therapy are more effective than conventional x-ray radiation.

There are no drugs currently approved to treat chordoma; however, several have shown modest benefit in clinical trials, such as the following:

• Pemetrexed: 14% objective response rate with median progression free survival of 10.5 months
• Pembrolizumab: 12% objective response rate with median progression free survival of 6.1 months
• Afatinib: 10% objective response rate with median progression free survival of 8.6 months
• Apatinib: 3% objective response rate with median progression free survival of 18 months
• Imatinib: 2% objective response rate with median progression free survival of 9.2 months

Prognosis

In one study, the 10-year tumor free survival rate for sacral chordoma was 46%. Prognosis depends on many different factors. With appropriate treatment, many chordoma patients will live for a decade or more, and some can be cured.

Epidemiology

In the United States, the annual incidence of chordoma is approximately 1 in one million (300 new patients each year).

Sacral chordomas make up 2 to 4% of all primary bone tumours and 44% of all primary sacral tumours, thus making it the most common malignant sacral tumor. About 50 to 60% of chordomas are located in the sacrococcygeal region. Males aged between 40 and 50 years are twice as likely as women to get sacral chordoma.

There are currently no known environmental risk factors for chordoma. As noted above germline duplication of brachyury has been identified as a major susceptibility mechanism in several chordoma families.

While most people with chordoma have no other family members with the disease, rare occurrences of multiple cases within families have been documented. This suggests that some people may be genetically predisposed to develop chordoma. Because genetic or hereditary risk factors for chordoma may exist, scientists at the National Cancer Institute are conducting a Familial Chordoma Study to search for genes involved in the development of this tumor.

Notable cases

NFL player Craig Heyward was treated for a chordoma in 1998, which ended his career. While initially thought to be successfully removed, the tumor returned in 2005, and caused Heyward's death in May 2006.

Pro skateboarder Ray Underhill, a member of the Powell-Peralta Bones Brigade, battled chordoma for two years before succumbing to his disease in August 2008.

Cary Tennis, the popular advice columnist for Salon, announced in his column of November 19, 2009, that he had been diagnosed with a chordoma.

Former Spanish footballer José Enrique was diagnosed with chordoma in May 2018 and underwent surgery to remove the tumour in June of that year. As of 2022, he is doing well.

Gary Sinise's son, McCanna "Mac" Anthony Sinise, who was a musician, died on January 5, 2024 at the age of 33 from chordoma. He had been diagnosed with chordoma in 2018 and eventually became paralyzed from the waist down. Shortly after his passing, his family established the Moving Ahead for Cures (MAC) Fund in his honor with the goal of accelerating the development of new treatments for chordoma.

Prominent British scientist, Paul Workman, lost his mother, Ena, to chordoma in 1989 at the age of 68.

References

References

1. National Cancer Institute. (February 27, 2019). "Chordoma".
2. "Primary Malignant Bone Tumors: Tumors of Bones and Joints: Merck Manual Professional".
3. (May 2016). "Extra-axial chordomas". Annals of the Royal College of Surgeons of England.
4. (2012). "Chordoma: current concepts, management, and future directions.". Lancet Oncol.
5. (September 2004). "Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2". Genes Chromosomes Cancer.
6. (March 2009). "Aberrant Hyperactivation of Akt and Mammalian Target of Rapamycin Complex 1 Signaling in Sporadic Chordomas". Clinical Cancer Research.
7. (May 2009). "Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway". British Journal of Cancer.
8. (February 2008). "Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma.". Neuropathology and Applied Neurobiology.
9. (January 2008). "Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation.". British Journal of Cancer.
10. (March 2009). "Chordoma and chondrosarcoma gene profile: implications for immunotherapy.". Cancer Immunology, Immunotherapy.
11. (2009). "Gene Duplication Identified in an Uncommon Form of Bone Cancer".
12. (November 2015). "Familial Chordoma: a case report and review of the literature". Oncology Letters.
13. (2015-02-19). "First clinical guidelines for chordoma treatment published in ''The Lancet Oncology''".
14. (November 2007). "Chordoma: the nonsarcoma primary bone tumor". The Oncologist.
15. Stacchiotti, S.. (2015). "Building a global consensus approach to chordoma: a position paper from the medical and patient community". Lancet Oncology.
16. (2017-06-01). "Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group". Annals of Oncology.
17. (2006). "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.
18. "Surgery".
19. (2009). "Sacral chordomas: Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas.". Int J Radiat Oncol Biol Phys.
20. (2023-12-04). "Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma". Clinical Cancer Research.
21. (August 2023). "Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial". The Lancet. Oncology.
22. (June 2024). "A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first line or later line treatment in advanced chordoma.". Journal of Clinical Oncology.
23. (September 2020). "Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study". The Lancet. Oncology.
24. (2012-03-20). "Phase II study of imatinib in advanced chordoma". Journal of Clinical Oncology.
25. (2005). "Operative management of sacral chordoma". The Journal of Bone and Joint Surgery. American Volume.
26. "Frequently asked questions".
27. "College student fights his own cancer - Yahoo! News".
28. (January 2021). "Demystifying Sacral Masses: A Pictorial Review". The Indian Journal of Radiology & Imaging.
29. (2014). "Familial Chordoma Study of the T Gene". Hum Genet.
30. "Familial Chordoma Study".
31. "Remembering Nashville Skateboard Legend Ray Underhill".
32. "José's Uncommon Story".
33. (February 27, 2024). "Gary Sinise's Son McCanna Dead at 33 After Rare Cancer Battle". ET Online.com.
34. "Moving Ahead for Cures (MAC) Fund: The Mac Sinise Fund to Accelerate…".
35. McKie, Robin. (2025-02-15). "British professor makes 'thrilling' breakthrough for cancer that killed his mother". The Observer.