This information has been written for patients, their families and friends and the general public to help them understand more about a rare form of primary bone cancer, known as chordoma. This section will detail what a chordoma is and how a chordoma is diagnosed and treated.
For a downloadable source of this information, please view our 'Downloadable Information Materials' page to view all of our fact sheets.
Chordoma is a rare form of primary bone cancer, known to affect only 1 individual per 800,000 people every year (1). They account for less than 5% of all primary bone tumours. Chordomas affect males more commonly than females (1.5:1 male: female ratio). Approximately 60-65 people are diagnosed with chordoma each year in the UK and Ireland. The median age of diagnosis is 58 years and they are very uncommon in patients under 30 years of age (1, 2).
Chordomas most frequently arise in the skull base, along the spine and the sacrum. The different locations of these tumour lead to varying symptoms. This variation of symptoms, and the slow-growing nature of the tumour often make the diagnosis of a chordoma difficult and lengthy.
50% of chordomas are reported in the sacrococcygeal region of the spine, which is the very base of the spine where it connects to the pelvis. A further 35% occur in the base of the skull where the skull meets the spine (known as the spheno-occipital region, often affecting a region of the occipital bone called the clivus) and the remaining 15% present in the vertebral column; which includes all areas along the main length of the spine (2).
This tumour type is thought to develop from tissue known as the notochord (pronounced no-tow-cord). This is the most widely accepted hypothesis, but there is no strong evidence to univocally support this. The notochord is required during embryonic development to form the template of spinal tissue while the baby is in the womb. Over time, this developmental structure is replaced with bone and there is no use for the notochord in adults. Small areas of the notochord are likely to remain into adulthood in many individuals with no effect. However, like any other cell type, these small areas of remaining notochord are capable of being transformed into cancerous cells which grow uncontrollably to form a chordoma tumour (3).
Most chordomas are low-grade tumours, meaning they are slow-growing and unlikely to spread elsewhere in the body (2,4). However, they can become locally aggressive and cause bone destruction in neighbouring areas. If an advanced chordoma does spread (a process known as metastasis), it will most commonly affect the lungs, nearby lymph nodes, the bones, the liver or the skin (5).
The yearly incidence of chordoma is approximately 1 case in every 800,000 people, with approximately 60-65 people being diagnosed with chordoma each year in the UK and Ireland (1). There is a slightly higher frequency of chordoma in males than in females and reports state that this tumour type is more common in Caucasian individuals(1,6).
Chordomas can develop in anyone, at any age, and have been diagnosed in patients from 3 to 95 years of age. Despite this, this rare tumour type is more common in adults around the age of 40 to 75 years; with a median age at diagnosis of 58 years(2). Children and adolescents are rarely diagnosed with chordoma and make up just 5% of cases. It is reported that chordomas arising in the skull often present at a much younger age in children and adolescents. However, this may be because chordomas of the skull present with symptoms earlier, leading to an earlier diagnosis(4).
The slow-growing nature of chordoma means that patients are often symptom free until the tumour has developed to a certain size.
As chordomas are located in the spine and the skull they frequently present close to major nerves. Therefore, some of the first symptoms chordoma patients experience may be caused by the tumour pressing on these nerves, causing nerve-based symptoms known as neurological effects(4).
The neurological effects of a chordoma include:
- Numbness in the limbs
- Tingling sensations
- Pain in the back, neck or head
Chordomas can develop at the base of the spine, the main part of the spine, the neck or the skull. Due to the various locations, these tumours present with different symptoms and signs depending on the location. As these symptoms are often non-specific and could often mimic those of more common conditions, it can take a long time for a chordoma diagnosis to be made.
The varying locations of a chordoma and their relative symptoms are:
Tumours in the base of the spine (known as the sacrococcygeal region):
- Lower back pain – which is often dull and becomes worse when sitting
- Tenderness of the lower back
- A lump on the lower back
- Pain in the legs
- Weakness or numbness in the lower back or the legs
- Constipation – this is because the tumour may press on the bowel
- Loss of bladder control – this is because the tumour may press on the bladder or affect the nerves connected to the bladder
Tumours in the main part of the spine (known as the vertebral column):
Tumours in the neck (known as the cervical region):
- Breathing obstruction
- Neck pain
- Difficulty swallowing
Tumours in the base of the skull (known as the spheno-occipital region):
- Facial pain
- Disturbances to vision – such as double vision, difficulty focusing the eyes or rapid eye movements
- Paralysis of facial nerves – causing swallowing, speech and eye movement abnormalities
- Nausea – which is the feeling of being sick
- Fatigue – which is the feeling of extreme tiredness
For more information on the symptoms of primary bone cancer, please refer to our About Primary Bone Cancer information section
There are three known types of chordoma; classic chordoma (also known as conventional chordoma), chondroid chordoma and dedifferentiated chordoma(1,4).
These classifications are based on the appearance of these tumours on imaging tests and under the microscope. The specific type of chordoma can be distinguished by radiologists (who assess images of the tumour that are created during scans) or by pathologists (who assess the types of cells in the tumour under a microscope following a biopsy).
The three types of chordoma are:
- Classic/Conventional Chordoma: Classic chordomas are the most common type of chordoma - accounting for around 80-90% of all cases
- Chondroid Chordoma: Chondroid chordomas make up between 5 to 15% of all chordoma cases and most frequently arise in the base of the skull(4). This type of chordoma has some similarities to a more common form of primary bone cancer, known as chondrosarcoma (which is a tumour developing from the cartilage). These similarities are due to a chondroid chordoma being made up of a mix of chordoma cells and abnormal cartilage cells
- Dedifferentiated Chordoma: Dedifferentiated chordomas account for less than 5% of all reported chordoma cases(1). However, they are a more aggressive form of this tumour type. Although dedifferentiated chordomas can arise in all areas of the spine or skull, they are most commonly reported in the base of the spine in an area known as the sacrum(4).
Chordomas can also be classified on as ‘sporadic’ or ‘familial’:
- Sporadic Chordoma: Sporadic refers to a chordoma arising anew in a person who has no family history of chordoma. Sporadic chordomas are more common than familial chordoma
- Familial Chordoma: Familial chordomas are very rare. In these chordomas several members of the same family have, or have previously had, a chordoma. In some of these families the patient inherits extra copies of a gene called brachyury, which is associated with the development of a chordoma(7)
Almost all reported cases of chordoma have been known to occur randomly with no identified cause (7). However, there is some evidence to suggest that specific genes may be involved in the initiation and progression of chordoma. Additionally, in extremely rare cases, chordoma can develop in multiple members of the same family (known as familial chordoma) as a result of genetic risk factors.
Some causes and risk factors that increase the likelihood of an individual developing a chordoma are:
Chordomas have unusually high levels of a protein called brachyury that is normally found in the cells of the notochord, a precursor of the spinal cord. The brachyury gene (also called TBXT) which codes for the brachyury protein, is involved in controlling how the cells behave during human development; normally, after approximately 12 weeks, when its biological task is completed, the TBXT gene is switched off. If TBXT becomes reactivated in adulthood, it can contribute to the uncontrolled growth of cells and the development of cancer.
Many chordoma patients have a gene irregularity, known as a mutation, in the brachyury gene which may be associated with chordoma development in both familial and sporadic forms of the tumour (8).
Inheriting an extra copy of the brachyury gene is thought to be responsible for the familial form of chordoma in most cases.
Switching off the TBXT gene or indeed inactivating or promoting the degradation of the brachyury protein are therefore attractive approaches to find new therapies for cancer and chordoma specifically.
Receptor Tyrosine Kinases (RTKs)
Receptor tyrosine kinases (RTKs) are a class of proteins involved in mediating cell to cell communication and control many complex biological functions like cellular growth, proliferation, movement, metabolism etc. They are well known to be highly expressed in various cancer types, including chordoma. Their abnormal presence and activation make them a desirable therapeutic target, as drugs that inactivate them, can be used to help combat cancer.
RTKs that are highly expressed in chordoma are the platelet-derived growth factor receptor (PDGFR), the epidermal growth factor receptor (EGFR), both proteins receive signals from the blood stream and neighbouring cells to activate the growth and division of cells which ultimately leads to the uncontrolled growth of cancerous chordoma cells (10).
Tuberous Sclerosis Complex (TSC)
Tuberous sclerosis complex (TSC) is a rare syndrome causing abnormal tissue growth in major organs. This results in rashes of the skin and problems in the kidneys, heart and nerves.
TSC syndrome is caused by mutations in genes known as TSC1 or TSC2. These mutations result in a lack of control over the cells growth and proliferation. It is this uncontrolled cell growth that causes cancer, and in this case, a chordoma (9)
70% of TSC syndrome cases are diagnosed during childhood, and many reports link the mutation of genes TSC1 and TSC2 to the development of childhood chordomas (9)
Mutations in TSC1 and TSC2 result in the activation of PI3K/Akt/mTOR proteins which in turn reduces cancer cell death and promotes cancer cell growth and proliferation. Drug molecules that inhibit mTOR, PI3K, or Akt are considered a potential therapeutic option, as they may reduce chordoma cellular proliferation and trigger cell death (23).
Vascular Endothelial Growth Factor (VEGF)
Vascular endothelial Growth Factor is a signalling protein that stimulates the growth of blood vessels from pre-existing ones, this process, known as angiogenesis, enriches the blood supply to the tumour, supplying it with nutrients and oxygen and facilitates metastasis.
VEGF and the proteins they interact with, known as VEGF receptors (VEGFRs), are highly expressed in the majority of chordomas (24, 25).
VEGF is a therapeutic target for chordoma and agents that inactive VEGF itself or VEGF receptors (VEGFR1 and VEGFR2) - angiogenesis inhibitors - are considered potential methods of treating chordoma.
VEGF production is stimulated by the low oxygen conditions (hypoxia) often found within solid tumours. A protein named Hypoxia-inducible Factor 1-alpha (HIF1a) that plays a key role in driving the cellular responses to low oxygen environments and is responsible for VEGF production, HIF1a has also been considered as a therapeutic target in chordoma.
Immune Check Point inhibitors
The interaction between Programmed Cell Death Protein1 (PD-1) and its ligands PDL-1 and PDL-2 plays a key role in supressing the immune system. Is a normal part of our immune system and its designed to avoid constant “overreactions.”
Cancer cells take advantage of this mechanism, to avoid being attacked by the immune cells that would normally destroy them (26).
Immune check point inhibitors disrupt the interaction between PDL-1 (on the cancer cell) and PD-1 (on the surface of T-cells), allowing immune cells to recognise and attach the cancer cells; they have received great attention and this type of immune therapy is now being investigated for a number of cancers, including bone sarcomas (26).
PDL-1 has been shown to be expressed in chordoma cells (27).
Agents like Nivolumab that block PD-1 on the surface of immune cells, can prevent its binding to PDL-1 and are being considered as potential therapeutic agents in chordoma (28).
Changes to the way the genetic code is expressed, without alteration of the DNA code sequence, are known as epigenetic modifications. In cancer cells, these changes can lead to the activation of tumour promoting genes (oncogenes) and the silencing of tumour suppressor genes.
The three main epigenetic mechanism include DNA methylation, histone modifications post-transcriptional gene regulation by non-coding RNA (miRNA). All three are found in chordoma and they lead to tumour cell growth and proliferation (29).
Histones are proteins involved in the coiling and aggregation of DNA into the more densely packed structures in chromosomes. The modification of histones is mediated by certain proteins, for example Enhancer of zeste homolog 2 (EZH2). Inhibitors of EZH2 like Tazemetostat are being investigated as potential therapeutic treatments for chordoma (30).
Patients with different types of primary bone cancer are assessed in similar ways. For this reason, diagnostic tests are covered in more detail in our About Primary Bone Cancer information section.
This section aims to provide information on the specific details of diagnosing a chordoma and to discuss other conditions that may appear diagnostically similar to a chordoma.
Going to the doctor
The symptoms of a chordoma are non-specific and depend on the exact location of the tumour. Patients often present with back pain which can be easily overlooked and therefore chordomas can take a long time to diagnose. An accurate diagnosis is important to plan treatment and ongoing care.
The first step in diagnosing any primary bone cancer is usually a trip to the GP. Diagnosis of a suspected bone tumour usually follows a clinical examination and an X-ray or a scan. It is very common to be referred to a bone cancer specialist for a second opinion and confirmation of the diagnosis.
Further diagnostic tests to confirm the presence of a chordoma include: X-rays, CT scans, MRI scans, a biopsy of the bone and blood tests.
More information on X-rays, CT Scans, MRI scans, bone biopsies and blood tests can be found here.
X-rays, CT (computerised tomography) scans and MRI (magnetic resonance imaging) scans cannot definitively diagnose a chordoma. However, these scans can provide important information on the location of the tumour, the stage of the tumour and can determine if the chordoma has spread elsewhere in the body.
A biopsy is a specialist procedure that takes a small sample of the tumour so it can be examined under a microscope. A needle biopsy is taken most frequently, which requires the insertion of a needle into the tumour to draw out a small sample of the affected bone tissue. Taking a biopsy of the bone can be used to confirm the diagnosis of a chordoma but may be combined with an operation to remove the tumour in some cases at the skull base.
Not all base skull chordomas will undergo a biopsy before being resected. Some cases will have an excisional biopsy since the risks of undergoing a surgical biopsy at the base of the skull may be similar to those of having an operation to resect the tumour. Each case must be decided by the MDT on an individual basis.
Results from a biopsy can take up to two weeks to analyse and they enable doctors to confirm the presence of a chordoma and the specific type of chordoma that is presenting.
To learn more about biopsies please see our ‘About Primary Bone Cancer’ information section.
An alternative diagnosis
When diagnosing a chordoma, it is important to eliminate the presence of various other diseases, or conditions, which may have similar signs, symptoms and diagnostic appearance to chordoma. It is important that the correct diagnosis is made to ensure the treatment provided is suitable(1).
It can sometimes take a long time to confirm a diagnosis of primary bone cancer after a biopsy, this is because these tumours are rare and sometimes difficult to identify. Diseases with similar symptoms or signs are known as ‘differential diagnoses’.
There are numerous conditions which present in a similar way to chordoma. Just a few examples are listed, including:
- Benign Notochordal Cell Tumour (BNCT): BNCTs are non-cancerous tumours occurring in a similar location to a chordoma. These tumours often undergo further investigation to ensure the presence of a cancerous chordoma is ruled out. Unlike chordomas, BNCT’s do not cause bone destruction to the surrounding area, which allows MRI and CT scans to differentiate between the two tumours (12). It can be difficult to say for certain whether a lesion is a BNCT or a chordoma on scans alone so sometimes a biopsy is needed to rule out a chordoma but will not be needed in every case.
- Metastatic Carcinoma: A cancer that spreads from one area of the body to form a tumour in another area of the body is known as a metastatic carcinoma. Many cancers spread to the bone, including those from the breast, lung, prostate and kidney(1)
- Chondrosarcoma: Another form of primary bone cancer
- Osteosarcoma: Another form of primary bone cancer
- Giant Cell Tumour of the Bone: A non-cancerous tumour that arises in the bone
If a diagnosis of chordoma is confirmed, you will need treatment in a bone cancer surgical centre.
For more information on the locations of bone cancer surgical centres please click here.
Chordomas are usually unresponsive to conventional radiotherapy and cytotoxic chemotherapy, making surgery the primary therapeutic option. However, the complex anatomy of the spine and the relatively large tumour volume often make a clean surgical resection technically challenging, leading to a high rate of local relapse and distant metastases. Therefore, novel therapeutic strategies are needed to improve patients' survival and improve their quality of life (c,d).
This cancer type is one which has received a lot of research attention. Scientists are working to develop advanced radiotherapy techniques and targeted treatments to specific gene alterations taking place in the tumour to improve the treatment of chordoma (see 'Causes, Risk Factors & Therapeutic Targets in Chordoma' section for more information).
As with in the majority of primary bone cancers, the main treatment option for chordoma patients is surgery (4). The slow-growing nature of this tumour type, and its low risk of spreading to other areas of the body, makes the surgical removal of the tumour a beneficial method of treatment. The removal of the tumour alongside a small amount of healthy tissue reduces the risk of the tumour returning at a later date and ensures all cancer cells are removed from the area. This procedure is known as taking a ‘wide-surgical margin’(1).
Unfortunately, the location of a chordoma can often make the planning of surgical margins difficult. Chordomas present on the spine and the skull and are therefor frequently located nearby to major nerves, structures and critical organs(4). If the tumour is present at the base of the skull, surgery can often be carried out using a tube through the nose - which is known as an endoscopy. The location of the tumour may also mean that it is not always possible to remove a margin of healthy tissue too.
The complete surgical removal of the chordoma offers the best chance of controlling the cancer (4). However, as there is not much space around these tumours and nearby critical structures, the tumour is often removed and radiotherapy is carried out to destroy any remaining cancer cells in the area. Therefore surgery followed by radiotherapy treatment offers the best possible control of the chordoma and lowers the probability of the tumour returning at a later date.
In some cases, due to the location of the tumour, surgery may not be possible and other treatment will be used as an alternative. As chordoma is commonly located on the spine, surgery can have effects on the patient’s lower limb, bladder or bowel functionality. Therefore, the benefit of surgery must be assessed alongside the possible risks and side-effects.
Radiotherapy is used following surgery to ensure all cancer cells in the area are destroyed. Radiotherapy is not usually used on its own for the treatment of chordoma, as a very high dose of radiotherapy is needed to kill the cancerous chordoma cells.
This high dose of radiotherapy may damage the nerves that are nearby to the tumour, and so this method tends to only be used when surgery is not an option. Surgery may not be possible if the tumour is present in an inoperable location or if a previous surgical procedure provided inadequate therapeutic results.
Additionally, radiotherapy may be of use to patients as a form of symptom and pain management – referred to a ‘palliative radiotherapy’ (5).
Proton Beam Therapy
What is it?
Proton Beam Therapy (PBT) is a type of radiotherapy that uses beams of 'protons' (energised particles), instead of beams of X-rays (photons), that are used in conventional radiotherapy. It is more targeted than conventional radiotherapy so does less damage to the healthy tissue surrounding the tumour and other organs. This is advantageous for some primary bone cancers where the cancer is close to a critical part of the body such as the spinal cord.
What is the difference between PBT and radiotherapy?
As proton beam therapy is highly targeted towards the tumour, it means it is often possible to treat areas closer to very sensitive structures such as the spinal cord. Overall, this means that fewer healthy cells nearby receive a dose of radiation. This is particularly important in children, whose bodies and structures are still developing.
Who might benefit from it?
The main advantage of PBT is that it can deliver a more targeted use of radiotherapy than X-ray radiotherapy. This is particularly beneficial to children and young adults with a primary bone cancer, as it avoids damaging healthy, developing tissues and is thought to reduce the risk of secondary malignancies later in life.
For adults, it is considered beneficial for tumours in areas where surrounding tissue is highly sensitive to the effects of radiation. For example, primary bone cancers in a sharply defined areas such as Ewing sarcomas, osteosarcomas of the spine or pelvis as well as chordomas are often suitable for PBT.
One of the key advantages of proton beam therapy over conventional radiotherapy is that it is more targeted. It does less damage to the healthy tissue around the tumour and the rest of the brain. This means it causes fewer side-effects, however, there are a few side-effects which are not uncommon.
The following side-effects are usually temporary and often disappear after treatment has finished:
- redness that resembles sunburn - this can appear in the area where the proton beam was directed
- hair loss.
How can I access PBT?
PBT is now available in UK through NHS. There is an NHS Centre at the Christie Hospital, Manchester as well as a second NHS PBT Centre planned for University College Hospital London (UCLH) due to open soon in 2021.
All PBT is approved by the Proton Clinical Reference Panel. The NHS will cover the cost of PBT treatment at approved treatment centres, whether in the UK or in the USA, Germany and Switzerland. If sent abroad for PBT, it will also fund economy travel and approved accommodation for the patient (children) and one to two carer(s)/parent(s) and one parent/carer for teenage and adult patients, accompanying them.The NHS will not fund any meals or refreshments, nor any upgrades to travel or accommodation. If you need help to cover travel costs not subsidised by the NHS, contact our Support & Information Service about our Travel Assistance Grant and other financial help that may be available.
Chemotherapy is the use of drugs to destroy the cancer cells in the body. This mode of treatment is used in many cancers and enters the blood stream to target cancer cells that may have spread elsewhere in the body.
In general, chordomas do not respond to chemotherapy and therefore it is not often used in the manner that it may be in other cancer types (4). The exception is a variant known as dedifferentiated chordoma.
Dedifferentiated chordomas are high grade tumours which make up just 5% of all chordoma cases. This tumour type is often sensitive to chemotherapy and so drugs may be used as part of the treatment.
The chemotherapy drugs used to treat dedifferentiated chordomas include:
- Anthracyclines (such as Doxorubicin): these drugs inhibit DNA replication and prevents cell division
- Cisplatin: this drug triggers the death of cancerous cells
- Alkylating Agents: these drugs bind to DNA and prevents its replication
There is ongoing research into the development of targeted drug therapies, which target a specific molecule that may be overexpressed or mutated in this cancer type and not in healthy cells. Development of targeted drug treatments may help improve survival for chordoma patients.
Researchers have identified specific genes which show increased expression levels and activity in chordoma. These specific genes may become ‘molecular targets’ for targeted drug treatments which have the potential to be safer and more specific than conventional chemotherapy agents.
The main molecular targets of chordoma that have been identified are:
- Platelet-Derived Growth Factor Receptor (PDGFR):
PDGFR is a protein receptor initiating the growth and progression of many cancer types. 70-75% of chordomas express PDGFR in high
levels. This protein receptor has been targeted with a drug known as Imatinib. Clinical trials using Imatinib in chordoma have shown some success in treating patients and reducing the size of the tumour. However, the response to Imatinib is often short-lived and variable and so further clinical trials are continuing in this area(2,17,18).
- Epidermal Growth Factor Receptor (EGFR):
EGFR is a protein receptor initiating the growth and progression of many cancer types. 70% of chordomas express EGFR in high levels(8).
EGFR can be directly targeted with various drugs, including Erlotinib, Cetuximab and Gefitinib10. Erlotinib has shown some promising results in stabilising the disease when tested in a small amount of chordoma patients. However, more clinical trials are required to determine if Erlotinib, or other drugs targeting EGFR, could be used as a standard treatment for chordoma in the future.
At the end of 2016, following research from Professor Adrienne Flanagan, the effect of a drug known as Afatinib will be tested in clinical trials due to its ability to inhibit the functioning of EGFR(18).
Sunitinib is a drug that can target both EGFR and PDGFR. It has been tested in a small number of chordoma patients and some of these patients responded well to this treatment. Further clinical trials will show whether Sunitinib could be used to treat chordoma patients in the future.
Additionally, alongside EGFR and PDGFR, other proteins involved in chordoma development are being investigated(8). These include; insulin-like growth factor receptor (IGF-1R) which is present in 76% of chordomas, vascular endothelial growth factor (VEGF) and STAT3(18).
Ultimately, targeted therapies are in the early stages of development and although further experiments are required, the results seen so far are promising.
For more information regarding treatment procedures, including surgery, chemotherapy and radiotherapy, please visit our About Primary Bone Cancer information page.
The outcome for chordoma patients is very dependent on the stage of the tumour, the location of the tumour and the type of tumour.
Although chordomas are unlikely to spread, the tumour returning at a later date (known as recurrence) is a large factor in worsening the prognosis of chordoma patients and the most important factor to consider when determining a patient's prognosis. The success, or failure, of surgery and radiotherapy treatment in destroying all cancer cells in the body correlates with the survival rate of patients; this is because any tumour cells left behind following treatment become capable of re-growing and forming a new tumour(19).
Ultimately, early diagnosis is key to achieving better control of the tumour and reducing the risk of recurrence.
It is important to bear in mind that patients receiving treatment outside of the UK may receive different tests and treatment in accordance to the guidelines set out in that specific country. If you have any questions or concerns regarding this please discuss this with your medical team or contact The Bone Cancer Research Trust for more information.
If you would like more information about chordoma please contact us.
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