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Giant cell tumor is a relatively common, locally aggressive, potential behavior, capacity to metastasize and benign neoplasm that is associated with a large biological spectrum ranging from latent benign to highly recurrent and occasionally metastatic malignant potential [rx]. It is one of the most common benign bone tumors, occurring in young adults ages 20–40 years with a high recurrence rate and a potential for aggressive behavior. It is most commonly located in the metaphysis or at the epiphysis of the femur or tibia. This activity reviews the evaluation and management of giant cell tumors and highlights the role of the interprofessional team in improving care for the patients with this condition.
A giant cell tumor is a rare, aggressive non-cancerous tumor. It usually develops near a joint at the end of the bone. Most occur in the long bones of the legs and arms. Giant cell tumors most often occur in young adults when skeletal bone growth is complete.
Giant cell tumor (GCT) is one of the most common benign bone tumors, which occurs in young adults 20-40 years old with a high recurrence rate and a potential for aggressive behavior.[rx] It is most commonly located at the metaphyseal or epiphyseal portion of the tibia or femur. While overall GCT has a benign characteristic, the disease behavior spectrum is extremely unpredictable. Local aggressiveness can range from focal symptoms due to bony or cortical destruction, up to surrounding soft tissue expansion and metastasis. An occurrence within the axial skeleton can lead to severe local complications and is usually unresectable.[rx]
The biopsied tissue have multinucleated giant cells under the microscope. They consist of three different cell types:
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giant cell tumor stromal cells of osteoblastic origin
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mononuclear histiocytic cells
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the multinucleated giant cell of an osteoclast-monocyte lineage.[rx]
The tumor bone resorption is primarily done by the giant cells. The spindle-like stromal cells recruit monocytes and promote their fusion into giant cells. The stromal cells also improve the resorptive ability of the giant cells.
Pathophysiology
The receptor activator of nuclear factor kappa B [NF-kB] ligand (RANKL) appears to be critical to the pathogenesis of GCT. Under normal physiologic conditions, osteoclast formation requires interaction with cells of the osteoblastic lineage, which may depend upon cell-cell contact, and the interaction of RANKL with its receptor RANK.[14] This receptor is highly expressed on monocytes, while RANKL is expressed by a variety of cell types, including stromal cells and lymphocytes. A variety of co-regulatory molecules also take part in osteoclast formation, including monocyte-colony-stimulating factor, vitamin D, parathyroid hormone and parathyroid hormone-related protein, and prostaglandins.[rx]
Several studies identified RANKL as highly expressed by the stromal cells within a GCT.[rx][rx] The stromal cells also secrete factors that can regulate or prevent osteoclastogenesis, including osteoprotegerin, which blocks osteoclast/osteoblast interactions and functions as a natural negative regulator of RANKL.[rx] The expression of RANKL by the osteoblast-like mononuclear stromal cells stimulates the recruitment of the osteoclastic cells from a normal monocytic pre-osteoclast cell. The osteoclastic giant cells then actively absorb host bone via a cathepsin K and matrix metalloproteinase 13-mediated process, which would account for the osteolysis associated with these tumors.[rx]
Mutations in the H3F3A gene, present in over 90% of GCT, may drive tumorigenesis. These mutations are restricted to the stromal cell population and are not detected in the osteoclasts or their precursors.[rx] The neoplastic stromal cell likely owns an immature osteoblast phenotype, part of whose transcriptional repertoire includes RANKL, besides other markers of the early osteoblast lineage.[rx] It is also postulated that the stromal cells have become activated not because of some inherent genetic change but instead from a local hemorrhage-induced release of red cells and plasma proteins into the matrix. Unknown reciprocal giant cell signals may be involved in maintaining the stromal cells’ immature state. RANKL has been identified as a primary molecular target for therapy.[rx]
Causes of Giant Cell Tumor
The exact etiology of GCT is not fully understood yet. It remains uncertain whether it is a true neoplasm or just a reactive condition. A 20q11 amplification is seen in 54% of GCTs, over-expression of p53 in 20% of them. Centrosome amplification, and boosted telomerase activity with the prevention of telomeres shortening support a neoplastic etiology.[rx][rx][rx]
Most often, the tumors occur close to the knee joint—either in the lower end of the thighbone (femur) or the upper end of the shinbone (tibia).
Other common locations include the:
- Wrist (lower end of the lower arm bone)
- Hip (upper end of the thighbone)
- Shoulder (upper end of the upper arm bone)
- Lower back (connection of the spine and pelvis)
Most giant cell tumors occur in patients between 20 and 40 years of age. Only rarely do they occur in children or in adults older than 65 years of age. They occur slightly more often in females.
Symptoms of Giant Cell Tumor
The following are the most common symptoms of a giant cell tumor. However, each person may experience symptoms differently. Symptoms may include:
- A visible mass
- Bone fracture
- Fluid buildup in the joint nearest the affected bone
- Limited movement in the nearest joint
- Swelling
- Pain at the nearest joint
The symptoms of a giant cell tumor may look like other medical problems. Always talk with your healthcare provider for a diagnosis.
Diagnosis of Giant Cell Tumor
On gross inspection, these lesions are characteristically chocolate brown, soft, spongy, and fragile.[rx] Yellow-to-orange discoloration from the hemosiderin could also be present. Cystic blood-filled cavities within the tumor are common.[rx] Examination reveals a variable degree of cortical expansion and disruption with an intact periosteum.[rx]
Histologically, the lesions are cellular. Although the multinucleated giant cell is the characteristic cell type, these lesions have a background network of mononuclear stromal cells.[rx] The mononuclear cells could be plump, oval, or spindle-shaped. They could have prominent mitotic activity, but cellular atypia is rare. Multinucleate giant cells have numerous centrally located nuclei in opposition to the peripherally located nuclei of Langerhans-type giant cells seen in atypical infections. The nuclei are compact and oval and contain prominent nucleoli. Giant cells are distributed throughout the ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion. The concentration of multinucleated giant cells differs from tumor to tumor. Some tumors have numerous multinucleated giant cells, whereas others have a small number of giant cells settled in whirls of spindle-shaped stromal cells. In approximately 5% of the cases, giant cells invade the small perforating vessels.
Three types of cells are found in benign bone GCT:[rx]
- Type I cells look like interstitial fibroblasts, make collagen, and can proliferate. This cell is probably the tumor component of GCT. Type I cells share features of mesenchymal stem cells. They have characteristics that suggest they could represent an early differentiation into osteoblasts.[rx]
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Type II cells are also interstitial but resemble the monocyte/macrophage family and could be recruited from the peripheral bloodstream.[rx] These cells are precursors of the multinucleated giant cells.
Significant level activity for insulin-like growth factors I and II are found in type II and type III cells but absent in type I cells, which suggests that these factors are essential in the development and regulation of GCT.[rx]
Genetically, 80% of individuals with GCT of the bone exhibit the cytogenetic abnormality of telomeric associations (tas), whereas half of the cells in the tumor show the tas abnormality.[rx] The RANK pathway is often reported to be involved in the pathogenesis of GCT. This pathway is a crucial signaling pathway of bone remodeling that plays a critical role in the differentiation of precursors into multinucleated osteoclasts and activation of osteoclasts leading to bone resorption.[rx]
The most common history and physical findings include
- Pain is the most common presenting symptom secondary to the mechanical insufficiency resulting from bone destruction.
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Swelling and deformity – are associated with more extensive lesions.
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A soft tissue mass or bump – can occasionally be seen and results from the cortical destruction and tumor progression outside the bone. It is often found close to the joint. Thus, a limited range of motion at the joint area is common.
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Joint effusion and synovitis – are also possible. At the time of diagnosis, approximately 12% of patients present with pathological fractures.[rx][rx] The pathologic fracture incidence at presentation is 11-37%. Presentation with a pathologic fracture is thought to show a more aggressive disease with a higher risk of local recurrence and metastatic spread.[rx][rx]
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The typical epiphyseal location – is found in 90% of the tumors. The tumor often extends to the articular subchondral bone or even abuts the cartilage. It rarely invades the joint and or its capsule. In those rare instances in which GCT occurs in a skeletally immature patient, the ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion is likely to be found in the metaphysis.[rx][rx] Only 1.2% of GCT involved metaphysis or diaphysis without epiphyseal involvement.
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The most common locations – for the tumor in descending order are the distal femur, the proximal tibia, the distal radius, and the sacrum.[rx] Fifty percent of GCT arise around the knee region. Other sites include the proximal femur, the fibular head, and the proximal humerus. A pelvic bone tumor is somewhat rare.[rx]
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Multicentricity – or the simultaneous occurrence of GCT in different sites occurs but is exceedingly rare.[rx][rx] Most commonly, GCT is a solitary ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion. Multicentric involvement (less than 1%) is much more clinically aggressive and has a propensity for the small bones of the hands and feet, which is totally different from the solitary lesions. Patients with multicentric lesions are generally younger than those with lesions elsewhere.
Imaging
The workup includes:
- X-ray – reveals a characteristic radiolucent, geographic appearance with a narrow transition zone found at the ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion margin. This margin, as opposed to that of many other benign lesions, lacks a prominent sclerotic rim. Calcification of matrix, periosteal reaction, and new bone formation are typically absent.[rx] It is an eccentric ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion in the epiphyseal portion with a tendency to extend up to a centimeter of the subchondral bone.
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Positron emission tomography – Modern imaging modalities to determine the extent of disease involvement include MRI, CT scan, functional positron emission tomography (PET), and bone scans.
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CT scans – give a more accurate assessment of cortical thinning, penetration, and bone mineralization than the plain radiographs. The presence of a primary bone formation within the tumor suggests primary osteosarcoma. CT scan chest may be indicated to look for pulmonary metastasis. The metastatic spread is most common in the setting of a local recurrence; therefore, a chest CT is recommended in patients with locally recurrent disease.
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MRI scan – helps assess the surrounding soft tissue integrity, such as the neurovascular structures or the extent of subchondral extension into adjacent joints. In the typical GCT, there is homogeneous signal intensity, and the ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।" data-rx-term="lesion" data-rx-definition="A lesion is an abnormal area of tissue such as a spot, wound, patch, lump, or ulcer. সহজ বাংলা: শরীরের অস্বাভাবিক দাগ, ক্ষত বা ফোলা অংশ।">lesion is well-circumscribed. They present with low signal intensity on T1-weighted images and intermediate signal intensity on T2-weighted images. Expansile hypervascular mass with cystic changes and heterogeneous low to intermediate signal intensity on T1-weighted images and intermediate to high intensity on T2-weighted images are its characteristic findings on MRI.[rx][rx] Huge amounts of hemosiderin account for the areas of low signal intensity on both T1 and T2-weighted images.[rx]
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A bone scan – can help stage multicentric disease, but findings of the bone scan, typically a decrease in the uptake of radiotracer in the tumor’s center, are not specific for GCT. Aneurysmal bone cysts have a similar appearance. There are limited data about the use of fluorine-18 fluorodeoxyglucose (FDG)-PET for newly diagnosed GCT. GCT accumulates the FDG tracer, unlike many benign bone tumors, presumably because of the active metabolism of osteoclast-like giant cells.[rx][rx] However, the advantages of evaluation with FDG PET as compared to conventional imaging with CT, MRI, or a bone scan are still unclear. Changes in FDG uptake over time correlate with the metabolism of the tumor and its angiogenic activity.[rx]
Treatment of Giant Cell Tumor
Nonsurgical Treatment
Nonsurgical treatment may include:
- Radiation. Radiation therapy may sometimes be used to shrink giant cell tumors in areas where surgery may be difficult to perform without damaging sensitive tissues—such as the spine. However, radiation therapy can result in the formation of cancer in some patients, so it is used only in the most difficult cases.
- Tumor embolization. During this procedure, specific arteries that supply blood to the tumor are blocked off. Without their supply of oxygen and nutrients, the tumor cells begin to die. Most often, embolization is performed prior to surgery, but it may also be used on its own in cases where surgery cannot be performed.
- Medication. The FDA has recently approved the use of an injectable medication for the treatment of giant cell tumors. The medication works by targeting a special receptor on the tumor cells. This decreases activity and slows down the breakdown of bone. The medication is sometimes used in cases where surgery cannot be performed or for recurrent tumors.
Surgical Resection
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Wide resection is correlated with a decreased local recurrence risk when compared with an intra-lesional curettage and could increase the recurrence-free survival rate from about 84% to 100%.[rx][rx][rx] However, wide resection is associated with higher rates of surgical complications and leads to functional impairment requiring reconstruction.[rx][rx][rx]
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Resection may be the preferred option even in benign tumors when the bone salvageability by intralesional methods would cause a severe compromise in mechanical characteristics. In the so-called “expendable bones,” such as the lower ulnar end, upper fibular end, excision may be the treatment of choice.
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Either in primary or recurrent cases, as the tumor involves the end of a long bone and causes significant dysfunction of the joint surface, reconstruction of the joint surface is necessary. A mega prosthetic joint replacement, a biologic reconstruction with an autograft arthrodesis with internal/external fixation, a microvascular fibula reconstruction, an Ilizarov method of bone regeneration, and an osteoarticular allograft are the options for those cases.[rx][rx]
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In the past GCT – was treated with amputations, wide resections, or reconstructions. But having in mind that GCT is a benign yet locally-aggressive tumor, a local intralesional surgical approach is appropriate in most cases. Curettage, curettage and bone grafting, curettage and insertion of polymethylmethacrylate (PMMA), and primary resection are among the recommended treatment options. Radiation therapy and embolization of the feeding vessels are used for pelvic and sacral tumors, which are not amenable to surgery.[rx]
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Radiotherapy – is also recommended for the spinal, sacral, or aggressive tumors when complete excision or curettage is impractical for any functional or medical reasons. Intralesional curettage and bone grafting are the limb-sparing treatment of choice, which is associated with acceptable functional and oncologic outcomes. However, a simple curettage with or without a bone graft has a recurrence rate between 27 to 55%. Many surgeons choose to replace bone graft packing of the lesion with PMMA packing due to the high recurrence rate.
Wide en-bloc resection is another option that offers the lowest recurrence rate and can be used in an expendable bone. In the proximal fibula, a wide resection without reconstruction is often performed. GCT of the distal radius is usually resected and reconstructed with an allograft or an autograft. -
Adjuvant treatments (liquid nitrogen, phenol, or HO and argon beam coagulation) offers an excellent recurrence-free survival, especially when paired with an intralesional curettage. A successful treatment for GCT heavily relies on the aggressiveness of the intralesional curettage than on the specific adjuvant used. The adequacy of tumor removal is influenced by the tumor location, associated fractures, extensions to the soft tissue, and an understanding of the functional consequences of the resection.
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Denosumab, a monoclonal antibody, is widely used to treat unresectable GCTs of bone in adults and skeletally-matured adolescents, and acts by specifically binding to RANKL.
There is no recognized effective chemotherapeutic agent available for the management of these tumors yet.
Key points about giant cell tumors
A giant cell tumor is a rare, aggressive non-cancerous tumor. It usually develops near a joint at the end of the bone. Most occur in the long bones of the legs and arms.
- Giant cell tumors most often occur in young adults when skeletal bone growth is complete.
- The exact cause of giant cell tumors remains unknown.
- Symptoms may include joint pain, swelling, and limited movement.
- Diagnostic tests may include X-rays, biopsy, and bone scans.
- The goal for treatment of a giant cell tumor is to remove the tumor and prevent damage to the affected bone.
- Tumors that can’t be removed surgically can often be controlled and sometimes destroyed with radiation therapy.
- Giant cell tumors can come back.
Next steps
Tips to help you get the most from a visit to your healthcare provider:
- Know the reason for your visit and what you want to happen.
- Before your visit, write down questions you want answered.
- Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
- At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
- Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
- Ask if your condition can be treated in other ways.
- Know why a test or procedure is recommended and what the results could mean.
- Know what to expect if you do not take the medicine or have the test or procedure.
- If you have a follow-up appointment, write down the date, time, and purpose for that visit.
- Know how you can contact your healthcare provider if you have questions.
References
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733230/
- https://www.cambridge.org/core/books/pearls-and-pitfalls-in-musculoskeletal-imaging/giant-cell-tumor-gct/B0DDA9D9D7C1ECF4F49757604DDA8DAC
- https://www.ncbi.nlm.nih.gov/books/NBK551681/
- https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq
- https://www.hopkinsmedicine.org/health/conditions-and-diseases/giant-cell-tumo
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598212/
- https://www.urmc.rochester.edu/encyclopedia/content.aspx?
