Updated: Dec 13, 2021
Chordoma is a rare, aggressive and invasive cancerous tumor of the bone involving the base of the skull, spine and sacrum . Chordoma cases have poor prognosis and are a part of a major group of bone and soft tissue tumors called sarcomas. Chordoma occurs in approximately one per one million individuals each year. Among the tumors affecting brain and the spinal cord, chordomas comprise < 1% . Chordoma is also referred to by other names such as Chordocarcinoma, Chordoepithelioma, Notochordal sarcoma, Notochordoma and CHDM. Most common locations of chordoma are the lower back and the base of the skull, about one-third to one-half of chordomas occur in the lower back or sacral area, and approximately one-third of chordomas occur in the base of the skull . In this article we provide a brief insight into this rare tumor.
Chordoma is considered to be a complex tumor because of its occurrence in locations comprising highly critical parts including the brainstem and spinal cord in association with important nerves and arteries . Chordomas grow slowly and gradually spread into the bone and associated encompassing soft tissue. Because of the slow and gradual process, it is asymptomatic at first and any symptoms associated with chordomas may persist for years before being properly diagnosed. In some cases, it is an aggressive tumor and is a recurrent tumor as well. In about 40% of the cases it has shown to metastasize to other parts of the body such as the lungs, liver, bones and lymph nodes , . Even though chordoma can occur at any age, it is usually seen in middle-aged groups of people (age 40 – 70). Chordomas occurring in the skull base are common in younger patients, whereas the spinal chordomas are seen in much older patients. Additionally, around 5% of chordomas are diagnosed in children. Chordomas are predominantly diagnosed in males compared to females with a ratio of 2:1 in adults although the reasons for this are unclear . Contrary to this gender difference in adults, pediatric chordomas are more common in females .
One of the main causes of chordoma are the notochord cells. Notochord is a structure in the embryo that facilitates the development of the spine. After approximately eight weeks of fetal development, the notochord disappears; however, in a small percentage of individuals some of its cells are left behind in the base of the spine and the skull base. In rare incidences, these residual cells grow and divide uncontrollably and invade nearby bone and the associated soft tissue leading to the development of the cancer called chordoma . The reasons for why the remaining notochord cells become cancerous is not completely understood and is an area of active research.
Genetic causes of chordoma include duplication of the TBXT (T-Box Transcription Factor T) gene . Cases of chordoma have shown higher expression levels of the TBXT gene; however, these changes are specific to the tumor cells. TBXT gene encodes for a protein called Brachyury which functions as a transcription factor within the T-Box family of genes. These proteins play a significant role during the embryonic development by regulating the activity of several other genes. Specifically, the Brachyury protein is important for early development of the spine. Increased levels of the TBXT gene leads to excess brachyury protein however it is still unclear how the excess levels of Brachyury protein leads to the development of chordoma. Surprisingly, some of the chordoma cases do not show any changes in the levels of the TBXT gene and the cause of chordoma in those cases are not known in detail. More than 95% of the chordoma cases have a SNP (Single Nucleotide Polymorphism), in the gene encoding Brachyury, leading to an increased risk of developing chordoma however this SNP by itself does not cause chordoma . Interestingly, the majority of the general population has this SNP as well; however, people with the SNP are unlikely to develop chordoma, with chances being less than two in one million people .
The majority of the chordomas that usually occur are random and sporadic . There are no known associated risk factors for chordoma in terms of environment, lifestyle and diet . According to the WHO classification of soft tissue and bone tumors there are three different types of chordoma, namely conventional chordoma, dedifferentiated chordoma, and poorly differentiated chordoma . The three different types are based on based on the histology and tumor cell characteristics. Conventional chordoma is the most common while the dedifferentiated chordoma is a rare chordoma occurring in < 5% of patients. Poorly differentiated chordoma is a very rare chordoma occurring in the younger group of people; however, it is more aggressive compared to conventional chordoma.
Symptoms of chordomas are specific to the exact location of the tumor . During growth, the tumor puts pressure on the adjacent areas of the brain and/or the spinal cord causing pain and nerve problems . Chordoma along the spine may lead to pain, weakness or numbness in different parts of body such as the back, arms or legs. Occipital chordoma which occurs at the skull base may lead to headaches and double vision. Coccygeal chordoma occurs in the tailbone and this may lead to problematic bowel and bladder function. Large chordomas can also result in a lump that can be felt through the skin.
Diagnosis of chordoma can be carried out using biopsy as well as imaging techniques including an MRI (magnetic resonance imaging) or CT (computed tomography) scan . Given the complexity of chordoma, prognosis is case specific. Prognosis depends on multiple factors such as age, type of chordoma, size and location of the tumor among other factors . Treatment options for chordoma include surgery, radiation therapy, radiosurgery, and targeted therapy . Notwithstanding the complexity of chordoma tumors, cases maybe survivable and possibly cured with appropriate treatment. Altered genes, proteins and signaling pathways may also be considered as therapeutic targets for chordoma directly and/or indirectly .
Kelly et. al. has carried out molecular characterization of chordomas with a study cohort comprising 68 chordoma cases . Immunohistochemistry results of the study showed frequent expression of EGFR, PTEN, PDGFR and c-MET. Next-generation sequencing analysis results showed mutations in ARID1A, TP53, PBRM1 including others. Bai et. al. studied 80 skull-base chordomas by whole genome sequencing and identified a significantly mutated driver gene called as PBRM1 which is a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene . Besides these published findings, there remain many unanswered questions regarding the causes of chordoma. The dearth of information creates new avenues of research in the field of this rare tumor.
Written by: Pawan Patro, Ph.D.
Keywords: chordoma, causes, symptoms, genes, brachyury
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“Understanding Chordoma.” https://www.chordomafoundation.org/learn/understanding-chordoma/.
W. Kelly, A. Anaizi, J. Xiu, and D. S. Subramaniam, “PATH-09. MOLECULAR CHARACTERIZATION OF CHORDOMAS INCLUDING TUMOR MUTATIONAL LOAD AND OTHER IMMUNE BIOMARKERS,” Neuro. Oncol., vol. 19, no. suppl_6, 2017, doi: 10.1093/neuonc/nox168.700.
J. Bai et al., “Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival,” Nat. Commun., vol. 12, no. 1, 2021, doi: 10.1038/s41467-021-21026-5.