Giant Cell Tumour of the Bone

Giant cell tumours of the bone tend to be benign (non-cancerous), but they can be locally aggressive.

Giant cell tumours of the bone are named due to the way they look under a microscope. Many ‘giant cells’ can be seen, which are cells that have formed due to the joining together (fusion) of several individual cells into one single, larger, cell. This production of giant cells can be seen in other conditions and cancers of the bone, as well as in normal bone. Therefore, confirming the diagnosis of a giant cell tumour of the bone is done after ruling out other giant-cell rich diseases - such as giant-cell rich osteosarcoma(2,3).

This tumour type typically occurs in the long bones of the body, including the thigh bone (the femur), the shin bone (the tibia) and the lower arm bone (the radius). Giant cell tumours of the bone tend to be at the end point of these long bones and are often found next to the joints. The most common location of a giant cell tumour of the bone is around the knee joint — where over 50% of giant cell tumours arise(4). Giant cell tumours of the bone can also start in the pelvis, the spine, the ribs, the skull and the sacrum — which is the base of the spine where it connects to the pelvis(2).

Giant cell tumours of the bone make up 4-5% of all primary tumours which start in the bone. However, for unknown reasons, this tumour occurs 2 to 3 times more often in Southern India and China — where giant cell tumours of the bone make up a much larger 20% of all primary bone tumour cases(1,3).

Some reports show a higher number of giant cell tumour of the bone cases in female patients than male patients(5,6).

80% of all giant cell tumours of the bone occur in patients aged between 20 and 45 years of age — affecting patients who have reached the full development of the skeleton (known as reaching skeletal maturity).

Although this tumour can also affect children and the elderly, this is rare(2,5,6).

Giant cell tumours of the bone grow slowly, and so the symptoms and clinical presentation of this tumour may not start until some time has passed. In some cases, the patient may not experience any symptoms at all — which doctors describe as ‘asymptomatic’(7).

The most commonly reported symptoms of a giant cell tumour of the bone are:

• Bone pain — pain tends to increase when active and improve when the area is rested
• Swelling
• A lump — with or without pain
• Tenderness
• Decreased mobility in the joint near to the tumour
• Build-up of fluid in a joint near to the tumour
• Fractures may occur due to the tumour weakening the bone –this is known as a pathological fracture

The location and size of the tumour can affect the symptoms that an individual patient may have. Tumours which develop on the spine, particularly in the sacrum, can lead to symptoms including:

• Back pain
• Neurological effects — such as weakness or numbness in the arms and legs and a sensation of pins and needles(7).

There is no identified cause or known origin of giant cell tumour of the bone. It is thought that these tumours arise spontaneously, without any apparent external cause, risk factor or predisposing factor(7).

The unknown cause of giant cell tumours of the bone has generated a lot of interest in researching this tumour type. This research has led to the hypothesis that a giant cell tumour of the bone can arise as a complication of a bone disorder known as Paget’s disease of the bone(2,6,8). Paget’s disease causes an alteration in the remodelling of the bone, creating weakened and disorderly bone tissue(8). On rare occasions, a giant cell tumour of the bone has been seen to arise secondary to Paget’s disease, and so this area continues to be investigated(6,8). For more information on Paget’s disease of the bone, please visit ‘The Paget’s Association’ at www.paget.org.uk.

A molecule known as RANK-L (or Receptor Activator of Nuclear factor κB ligand) has been investigated as a possible factor which influences the development of giant cell tumours of the bone. RANK-L is expressed in high levels on the giant cells which make up these tumours and many studies suggest this molecule to be responsible for the progression of giant cell tumours of the bone and the breakdown of the bone(3,7,8).

For this reason, a targeted treatment known as Denosumab has been developed to block the function of RANK-L and create a new treatment for giant cell tumours of the bone(7,8).

Patients with different types of tumours arising in the bone 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 giant cell tumour of the bone and to discuss other conditions that may appear diagnostically similar to Giant Cell Tumours of the Bone.

The symptoms of a Giant Cell Tumour of the Bone can be general. There is no one clear sign that doctors can easily look for to make a diagnosis of a Giant Cell Tumour of the Bone.

People report a variety of experiences when they seek medical advice about their symptoms. Most people with worrying symptoms go to their GP.

Some patients go to their local hospital emergency department (A&E) or other health care centres.

Some people are referred quickly for further tests or a second opinion, but often patients have to return to their GP three or four times before they are referred for more tests. Primary bone tumours are very rare and many GPs will never come across a case.

If a GP or hospital doctor is concerned about the patient's symptoms, there are national guidelines they should follow. According to the National Institute for Clinical Excellence (NICE) Guidelines for Suspected Bone Cancer and Sarcoma:

• Children, teenagers and young adults with unexplained bone swelling or bone pain should have an urgent X-ray within 48 hours. If the X-ray suggests a possible bone cancer, your GP should refer you to a specialist within 48 hours.
• Adults should be seen by a specialist within 2 weeks if the results of an X-ray suggest a bone cancer.

If the X-ray is normal but symptoms persist, the patient should be followed up and/or a repeat X-ray or MRI scan should be carried out within 2 weeks (adult) or within 48 hours (child) or a referral requested to a specialist.

Bone Cancer Awareness Initiative

The Bone Cancer Research Trust is trying to find ways to make the time between the start of symptoms and getting the diagnosis much shorter. Our 2020 Patient Survey report is the most comprehensive analysis of presenting symptoms and routes to diagnosis for primary bone cancers & tumours in the UK to date. This is our evidence base on which we will focus our awareness objectives moving forward.

The report focuses on two main areas - the time and routes to diagnosis and the range of presenting symptoms across all anatomical locations and forms of primary bone cancer & bone tumours.

Our analysis found that patients wait, on average, more than 7 months and make 8 visits to the multiple healthcare professionals before receiving an accurate diagnosis.

Going to a Bone Cancer Centre for more tests

Once an abnormality is found in a bone that suggests the possibility of cancer, the patient will be referred to a bone sarcoma surgical centre.

Bone sarcoma surgical centres are specialist hospitals. They have a group of healthcare specialists who are experts in the diagnosis and management of bone cancer.

In England, there are currently five bone sarcoma centres which specialise in the diagnosis and management of primary bone cancers. These centres are at Birmingham, Newcastle, Oswestry, Oxford, and Stanmore.

In the Republic of Ireland, there are no specific bone sarcoma centres. Patients are initially seen in their local hospital and subsequently referred to specialist hospitals in Dublin or Cork for further tests and, if necessary, for treatment.

Patients in Wales usually travel to Oswestry or Birmingham for these specialist tests.

In Scotland there are five sarcoma centres and so patients travel to one of these centres for diagnosis if primary bone cancer is suspected. These centres are in Edinburgh, Glasgow, Inverness, Aberdeen and Dundee.

In Northern Ireland, patients are usually seen in Belfast.

For a full list of locations patients may be referred to in order to confirm a primary bone cancer diagnosis please click here

The MDT

Specialists in many different areas of medicine at the bone cancer centres, the Regional Cancer Centres in the UK and hospitals in Ireland work together as a 'Multidisciplinary Team' (MDT). The members of the MDT work together to diagnose the patient's condition.

The MDT includes:

• Specialist sarcoma surgeons.
• Specialist sarcoma oncologists (oncologists are doctors who look after people with cancer).
• Specialist sarcoma pathologists (pathologists are doctors who use laboratory techniques to diagnose disease).
• Radiologists (doctors who diagnose disease and conditions from looking at x-rays, or scans).
• Sarcoma cancer nursing specialists (sometimes called 'CNS') who perform an essential role in treating and caring for primary bone cancer patients.

What tests are done?

When a person is referred to a bone cancer surgical centre, further tests will be done to find out more and to confirm whether the patient has bone cancer, and if so what type.

These tests may include:

X-ray

X-rays of the bone may be taken, including the joints above and below, and are studied. These X-rays may show swelling around the bone or areas of abnormal bone growth. A chest x-ray is sometimes taken to show whether the cancer has spread to the lungs.Cancer Research UK gives more information about X-rays.

Blood tests

These include:

• • Blood chemistry (Urea and Electrolytes) is checked to examine the levels of normal salts and urea and creatinine, which are waste products. This test can give clues to how well the kidneys are working
  • Full blood count (FBC) counts the numbers of different types of blood cells in the patient's blood at that time.
  • Red blood cells - which carry oxygen in the blood.
  • White blood cells - which are essential to the immune system (and totals of each type).
  • Platelets - which are essential to the making blood clots and scabs.
  • Levels of haemoglobin - which is found in red blood cells.
  • Liver function tests (LFTs) to see how the liver is working.
  • Erythrocyte Sedimentation Rate (ESR) is a test to look for signs of inflammation.
  • C-Reactive Protein (CRP) levels are tested as CRP levels increase in inflammation.
  • Alkaline phosphatase (ALP) levels are measured in patients with suspected osteosarcoma.

Cancer Research UK gives more information about blood tests.

MRI scan

MRI stands for 'magnetic resonance imaging'. This type of scan is similar to a CT scan but magnetism and radio waves are used instead of x-rays to build up a very detailed 3-dimensional image.

An MRI scan of the entire bone is used to gain more information about the tumour in the bone. An injection of a special dye, known as a contrast agent is also used. This makes certain tissues show up more clearly and with greater detail on the scan. The results of the scan will be examined by a radiologist and a report will be produced. For some patients they may also have a total body MRI scan to look for areas of abnormalities in the other bones such as tumour spread (metastases).

Cancer Research UK gives more information about MRI scans.

CT scan

CT stands for 'computerised tomography'. They may also be called CAT scans, which stands for 'computerised axial tomography'.

The scanner takes x-rays from many different angles and a computer builds up a 3-dimensional picture of the body in great detail. The pictures show cross-sections of the inside of the body.

CT scanning of the lungs shows up any secondary tumours where the cancer may have spread (metastases). It is used if the MRI scan results have not been able to confirm the diagnosis of osteosarcoma.

Cancer Research UK gives more information about CT scans.

A CT scan and MRI scan cannot definitively diagnose an adamantinoma. However, they provide important information on the exact location of the tumour, the stage of the tumour and the presence of the tumour having spread anywhere else in the body. Additionally, these scans are useful for planning the treatment of individual patients and deciding on the best way to surgically remove the tumour(2).

PET scan

PET stands for 'positron emission tomography.' Not all hospitals have PET scanners but they are used to detect spread or metastases in osteosarcoma.

PET scans can examine the whole body, rather than a specific area. They can also detect how well treatments are working.

Before the scan, a small injection of radioactive glucose (a radiotracer) called fluorine18 will be given.

The tracer will take around an hour to spread around the body. During the scan, which can last about an hour, the patient lies on a bed and the scanner passes over them. The scanner detects where the radiation is concentrated and produces images. Hot spots on the PET scan can detect metastases.

The results of the scan will be examined by a radiologist.

Cancer Research UK gives more information about PET scans.

Biopsy

Taking a biopsy of the bone is needed to confirm the diagnosis of a Giant Cell Tumour of the Bone. A bone biopsy is a specialised procedure that can be performed by a specialist in orthopaedic surgery or sarcoma radiology at a bone cancer surgical centre. A biopsy involves taking a small sample of a lump or tumour so that a pathologist can examine the cells in the sample and determine whether the lump is cancerous or not.

The biopsy being taken may be a ‘needle biopsy’ or an ‘open biopsy’.

• Needle biopsy: a needle is inserted into the tumour to draw out a small amount of tumour tissue (this may be done under local anaesthetic). Often, in order to know exactly where to take the sample from, this test is carried out alongside an X-ray or CT scan to guide the doctor.
• Open biopsy (or surgical biopsy): is used less frequently than a needle biopsy. This form of biopsy is carried out during a small, minor, operation to remove a small piece of tumour while under general anaesthetic. This test tends to be used if a needle biopsy does not provide a diagnosis and the doctor wish to investigate further.

Cancer Research UK gives more information about bone biopsies..

However, even with a biopsy, the accurate diagnosis of a giant cell tumour of the bone can still be difficult. Giant cells can be found in many other tumours, or may even be found where there is no tumour at all. Therefore, all other possible diagnoses must be ruled out before a giant cell tumour of the bone diagnosis can be made(3,6,7).

Furthermore, giant cell tumours of the bone often present alongside a substance known as osteoid — which is a component of the bone aiding bone production and development. The presence of osteoid is an important indicator of a common form of primary bone cancer, known as osteosarcoma. Consequently, if osteoid is detected, careful consideration of the tumour type presenting must be made in order to make an accurate diagnosis and provide the individual patient with the best possible treatment plan(7).

An alternative diagnosis?

When diagnosing a giant cell tumour of the bone it is important to rule out the presence of various other diseases, or conditions, which may appear in a similar manner to this tumour type in terms of signs and symptoms. It is important the correct diagnosis is made to ensure the treatment provided is suitable.

It can sometimes take a long time to confirm a diagnosis 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’.

Other conditions which can present in the same way as a giant cell tumour of the bone include:

• Giant-Cell Rich Osteosarcoma

This is a type of osteosarcoma (a more common form of primary bone cancer) which can appear similar to a giant cell tumour of the bone as both tumours have a large number of giant-cells and osteoid — a substance making up the bone(4,7). Benign giant cell tumours have the ability to change into an osteosarcoma and so care must be taken when differentiating between the two(6)

• Aneurysmal Bone Cysts

An aneurysmal bone cyst is a non-cancerous, blood-filled cyst which can develop in any bone in the body. These cysts grow in the bone, causing pain and possible fracturing of the bone - which are also seen in giant cell tumours of the bone(6)

• Brown Tumours

These non-cancerous tumours are rare and caused by the presence of an abnormally high level of the parathyroid hormone – known as hyperparathyroidism(7). On X-rays and under the microscope, they appear similarly to giant cell tumours of the bone and are differentiated by the high-levels of parathyroid hormone in brown tumours(7,9).

If a diagnosis of a giant cell tumour of the bone is confirmed, you will need treatment in a bone tumour centre.

For more information on the locations of Bone Cancer Centres please click here.

As giant cell tumours of the bone often appear near the joints, the main aim of treatment is to remove the tumour, to make sure that it does not return at a later date, while maintaining as much cosmetic and functional normality in the area as possible(1). Giant cell tumours of the bone have a very positive survival outlook of 90%(5,7).

Surgery

The most common method of treatment for a giant cell tumour of the bone is the surgical removal of the tumour. It is important that this surgery removes the entire tumour to ensure no tumour cells are left behind. The methods of surgery used are curettage or a wide surgical excision of the tumour.

Curettage surgery involves the removal of the tumour by scraping the tumour cells from the area. This is usually followed by ‘bone cementation’ – which aims to destroy any remaining tumour cells and fill the area following tumour removal to strengthen the affected bone. Bone cementation is usually carried out using a substance known as ‘polymethyl methacrylate’ (or PMMA). Other substances may also be used after curettage surgery, including phenol or liquid nitrogen, although it is not known if these reduce the risk of the tumour returning at the later date (known as recurrence)(4,11).

Ultimately, the risk of the giant cell tumour returning is down to the adequacy of the surgical procedure. A more invasive surgical procedure may be carried out if the tumour appears to be more aggressive. This procedure involves the removal of the tumour alongside a small amount of healthy tissue to ensure the whole tumour is removed — this is known as taking a ‘wide surgical margin’(5,11). This procedure lowers the risk of tumour recurrence but has a larger impact of the cosmetic and functional normality of the bone. Therefore, this method is reserved for more aggressive giant cell tumours or giant cell tumours of the bone which continue to return(4).

Chemotherapy

There are currently no reports that suggest there is benefit to using chemotherapy to treat giant cell tumours of the bone. However, drugs known as ‘bisphosphanates’ are occasionally used with the aim to reduce the risk of tumour recurrence(7).

Targeted Therapy

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.

A targeted drug known as Denosumab is commonly used to treat giant cell tumours of the bone, with the aim of destroying the giant cells which make up the tumour. Denosumab directly targets the molecule RANK-L, which is thought to influence the development of a giant cell tumour of the bone(2,3). Inhibiting RANK-L with Denosumab appears to stop the giant cells from destroying the bone, allowing the bone to heal so surgery can be performed with less impact to the cosmetic appearance and functionality of the affected bone.

Denosumab is often used before surgery to improve the surgical removal of the tumour. When a patient is being treated using Denosumab they will undergo regular X-rays to monitor how this drug is affecting the tumour and when the best time to operate would be.

Radiotherapy

Radiotherapy may be used after surgery to improve the control of the tumour. It may also be used to treat tumours that cannot be operated on due to their location - such as tumours on the spine(7).

However, radiotherapy must be used with caution in this tumour type as radiation can increase the risk of a benign, less aggressive, form of a giant cell tumour transforming to a malignant (cancerous) tumour at a later point in the patients life. This is known as a radiation induced sarcoma. Malignant tumours such as osteosarcoma, fibrosarcoma or malignant fibrous histiocytoma (MFH) have been known to develop from a giant cell tumour of the bone that has been treated with radiotherapy.

For more information regarding treatment procedures, including surgery, chemotherapy and radiotherapy, please visit our About Primary Bone Cancer information page.

Although giant cell tumours of the bone are non-cancerous, they have the ability to return at a later date (known as tumour recurrence) as a malignant (cancerous) tumour. The transformation of a giant cell tumour tends to occur if the tumour returns after a patient has received surgery or radiotherapy treatment(10).

Malignant tumours such as an osteosarcoma, fibrosarcoma or malignant fibrous histiocytoma have been known to develop from a giant cell tumour of the bone that has been treated with radiotherapy. The transformation of a benign giant cell tumour to a cancerous giant cell tumour can occur up to 20 years after the initial treatment and emphasises the importance of ensuring the surgical treatment of the tumour is adequate and there is little risk of the tumour returning at a later date (2,10).

Outcome

The outcome for patients with a giant cell tumour of the bone is very positive if the tumour is controlled and is not at risk of returning at a later date following treatment. This tumour is unlikely to spread to other areas of the body but on rare occasions (less than 6%) it may spread to the lungs or pelvis. However, this is still treatable and does not worsen the patients outlook dramatically(2,5).

Ultimately, it is important that a correct diagnosis is made and the use of surgery or biological therapies, such as Denosumab, are used efficiently to ensure the complete removal of the tumour.

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 treatment 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 giant cell tumours of the bone please contact us.

Key References:

1. Puri, A and Agarwal, M. Treatment of Giant Cell Tumour of the Bone: Current Concepts. Indian Journal of Orthopaedics. 2007; 41(2): 101-108. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC2989131/

2. Chakarun, C.J, Forrester, D.M, Gottsegen, C.J, Patel, D.B, White, E.A and Matcuk, G.R. Giant Cell Tumor of Bone: Review, Mimics, and New Developments in Treatment. Radiographics. 2013; 33(1). Available at: http://pubs.rsna.org/doi/full/10.1148/rg.331125089

3. Xu, S.F, Adams, B, Yu, X.C and Xu, M. Denosumab and Giant Cell Tumour of Bone — A Review and Future Management Considerations. Current Oncology. 2013; 20(5): e442-e447. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC380541...

4. Yacob, O, Umer, M, Gul, M and Qadir, I. Segmental Excision Versus Intralesional Curretage with Adjuvant Therapy for Giant Cell Tumour of the Bone. Journal of Orthopaedic Surgery. 2016; 24(1): 88-91. Available at: http://www.josonline.org/pdf/v24i1p88.pdf

5. Júnior, R.Z.B, Pires de Camargo, O, Ida, C.M, Baptista, A.M, Ribeiro, M.B, Bruno, J.M and Mendes de Oliveira, C.R.G.C. Primary Malignancy in Giant Cell Tumour: A Case Report. Sao Paulo Medical Journal. 2009; 127(5): 310-313. Available at:http://www.scielo.br/pdf/spmj/v127n5/v127n5a11.pdf

6. Greenspan, A, Kundt, G and Remagen ,W. Differential Diagnosis in Orthopaedic Oncology. Second Edition. 2007. Lippincott, Williams and Wilkins, Philadelphia. Available at: https://books.google.co.uk/books?id=pvIBdpQbLDEC&p...

7. Malawer, M.M, Helman, L.J, O’Sullivan, B. Devita, Hellmans, and Rosenberg’s Cancer: Principles and Pathology. Section Two: Sarcomas of the Bone. Volume Two: Eighth Edition. 2008. Lippincott, Williams and Wilkins. Philadelphia. Available at: http://sarcoma.org/publications/articles/devita.pd...

8. Cosso, R, Nuzzo, V, Zuccoli, A, Brandi, M.L and Falchetti, A. Giant Cell Tumour in a Case of Paget’s Disease of the Bone: An Aggressive Benign Tumour Exhibiting a Quick Response to an Innovation Therapeutic Agent. Clinical Cases in Mineral and Bone Metabolism. 2010; 7(2): 145-152. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC300446...

9. Giumarães, A.L.S, Marques-Silva, L, Gomes, C.C, Castro, W.H, Mesquita, R.A and Gomez, R.S. Peripheral Brown Tumour of Hyperparathyroidism in the Oral Cavity. Oral Oncology Extra. 2006; 42(3): 91-93. Available at: http://www.sciencedirect.com/science/article/pii/S...

10. Hashimato, K, Hatori, M, Hosaka, M, Watanabe, M, Hasegawa, T and Kokobun, S. Osteosarcoma Arising from Giant Cell Tumour of Bone Ten Years after Primary Surgery: A Case Report and Review of the Literature. The Tohoku Journal of Experimental Medicine. 2006; 208: 157-162. Available at: https://www.jstage.jst.go.jp/article/tjem/208/2/20...

11. Li, D, Zhang, J, Li, Y, Xia, J, Yang, Y, Ren, M, Liao, Y, Yu, S, Li, X, Shen, Y, Zhang, Y and Yang, Z. Surgery Methods and Soft Tissue Extension are the Potential Risk Factors of Local Recurrence in Giant Cell Tumour of Bone. World Journal of Surgical Oncology. 2016; 14: 114. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC483759...

Further Reading:

Futamura, N, Urakawa, H, Tsukushi, S, Arai, E, Kozawa, E, Ishiguro and Nishida, Y. Giant Cell Tumour of Bone Arising in Long Bones Possibly Originate from the Metaphyseal Region. Oncology Letters. 2016; 11(4): 2629-2634. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC481228...

Vera, L, Dolcino, M, Mora, M, Oddo, S, Gualco, M, Minuto, F and Giusti, M. Primary Hyperparathyroidism Diagnosed after Surgical Ablation of a Costal Mass Mistaken for Giant-Cell Bone Tumor: A Case Report. Journal of Medical Case Reports. 2011; 5: 596. Available at: https://jmedicalcasereports.biomedcentral.com/arti...

Zheng, K, Yu, X, Hu, Y, Wang, Z, Wu, S and Ye, Z. Surgical Treatment for Pelvic Giant Cell Tumour: A Multi-Centre Study. World Journal of Surgical Oncology. 2016; 14: 104. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482086...