Giant cell tumor of bone is an aggressive primary benign bone tumor composed of proliferating monocytes and osteoblast-like multinucleated giant cells with a propensity for local recurrence, and is also considered an intermediate or low-grade malignant bone tumor because of its ability to develop distant septal (pulmonary) metastases. This lesion has been recognized for more than a century, but it was not until the 1940s that it was considered a separate class of tumors from other lesions containing giant cells.
Chondroblastoma, mucinous fibroma of cartilage, simple bone cyst, hyperparathyroid brown tumor, nonossifying fibroma, aneurysmal bone cyst, and some osteosarcomas are all primary tumors of bone rich in giant cells. In Enneking’s surgical staging, they are usually localized as stage 3 tumors, while the more aggressive lesions are often localized as stage I tumors.
1. Epidemiological characteristics
The incidence of giant cell tumor of bone accounts for about 16% of all primary bone tumors in patients admitted to Beijing Jishuitan Hospital. The tumor usually occurs in patients with mature bones, and the age of prevalence is 20-40 years old, with very few patients developing before epiphysis closure. The incidence is slightly higher in women than in men, accounting for approximately 5614% of cases. In the age group below 20 years, the incidence is significantly higher in females than in males, accounting for 72% of cases. Giant cell tumor of bone mainly affects the bony end in adults and the epiphysis in children before epiphyseal closure.
The symptoms are mainly painful to varying degrees and may be accompanied by swelling and limitation of movement, with a duration ranging from a few weeks to several months. The most common sites are the distal femur, proximal tibia, distal radius, sacrum, distal tibia, proximal humerus, proximal femur and proximal fibula. Occasionally, it is seen in the small bones of the hands and feet, the vertebrae of the thoracolumbar segment and the ribs.
2.Imaging characteristics
2.1 X-ray plain film
For the imaging of giant cell tumor of bone, X-ray is the most valuable radiological examination for diagnosis. Giant cell tumor of bone shows osteolytic destruction of bone ends on X-ray, which may invade the epiphysis and extend to the articular side to invade part or all of the adjacent subchondral bone cortex. The size of the tumor is related to the size of the bone in which the lesion occurs. The extent of tumor invasion along the long axis of the affected limb is often smaller than that along the transverse axis, and sieve-like changes can be seen on the side of the diaphysis, while obvious swelling and thinning of the bone cortex can be seen around the bone end.
There is no periosteal reaction outside the cortical area, while periosteal reaction can be seen when a pathological fracture is present. There is usually an interruption of the subperiosteal new bone, but the periosteum remains intact and the marginal part of the cancellous bone may be clearly defined. Giant cell tumors do not have mineralization of the tumor matrix, and joint exudation is rare, although pathologic fractures often occur. Giant cell tumors of bone other than long bones have no characteristic radiographic appearance and are indistinguishable from other osteolytic lesions.
However, histologic diagnosis is still necessary before surgical treatment because similar imaging can occur in other lesions, such as malignant histiocytoma, osteosarcoma, and other tumors.
2.2 CT
CT is superior to radiographs in determining the extent of tumors. It can accurately determine the extent of the tumor within the cortex, the relationship of the tumor to other structures, the integrity of the cortex, and the extent of tumor invasion. In CT films, reactive changes and edema of the cortical surface and synovial membrane appear to be part of the tumor. In addition, non-enhanced CT cannot distinguish tumor from muscle because the attenuation coefficients between the two are the same, and CT can only show the extent of subchondral bone destruction by means of reconstruction. The fluid-fluid plane can be seen in the tumor, which is due to the combination of aneurysmal bone cysts with giant cell tumor of bone.
2.3 MRI
Magnetic resonance imaging (MRI) is the best imaging method for giant cell tumor of bone, with high quality contrast and resolution, and multiplanar imaging. Like most bone tumors, giant cell tumors show long longitudinal relaxation times (T1) and long transverse relaxation times (T2), whether in the horizontal, coronal or sagittal axes. The tumor shows low intensity signal in longitudinal relaxation time (T1) and high intensity signal in transverse relaxation time (T2).
CT cannot determine the extent of extracortical tumors, nor can MRI, because the tumor has the same attenuation coefficient as the adjacent muscle. It is better to identify small cortical disruptions with CT, because MRI has poor resolution for spatial presence.
2.4 Bone scan
Bone scans are also used in the diagnosis of giant cell tumor of bone, where the uptake of radionuclide 99mTc is increased at the site of giant cell tumor involvement. Elevated radionuclide uptake may be diffuse, with blood concentrated at the margins and less concentrated in the central portion. Radionuclide uptake can extend beyond the tumor boundary and therefore cannot be used to correctly determine the extent of invasion within the medullary cavity. Tumors located in soft tissue have low radionuclide uptake and cannot be used to determine the extraosseous extent of the tumor.
Increased uptake of radionuclides can occur in joints adjacent to the tumor, as well as in joints that are not invaded by the tumor. Bone scans are of limited use because they can neither confirm the diagnosis of giant cell tumor of bone nor determine the extent of tumor invasion. Bone scans can exclude or help to confirm multiple lesions.
In addition, angiography is rarely used as a diagnostic tool, and is only used to determine the relationship between large tumors and major blood vessels.
3. Histological features
The typical sites of giant cell tumor invasion are the epiphysis of long bones and the epiphyseal region of the tumor column of the stem musculoskeletal system. If left untreated, the tumor may spread to the diaphysis due to its large size. The tumor is usually eccentric to the long axis of the bone. In a few patients with unclosed epiphyses, the tumor may cross the epiphyseal plate from the epiphysis to the epiphysis. The bone on the inner side of the cortex is resorbed and the edges of the bone are invaded by the tumor, resulting in subperiosteal new bone, which forms a new shell around the tumor.
The tumor is gray or reddish brown in color and consists of soft blood vessels and fibrous tissue. The tough portion is grayish-yellow in color and is a fibrous and collagenous area, and the bone-like material may be the result of previous fractures and degeneration. Areas of necrosis and hemorrhage may lead to cystic transformation of the tumor. This presentation is very distinct and can sometimes resemble aneurysmal bone cysts.
It has been suggested that vascular infiltration is one of the causes of metastasis in giant cell tumors of bone, and it has also been suggested that the factor responsible for metastasis is previous surgery or radiation therapy, which may reveal osteoid material and small ossified lesions, especially in the periphery of the tumor. The link between the histological manifestations of the tumor and its biological behavior has proven to be unreliable, which is why the relationship between the two is no longer emphasized. The histologic pattern, imaging features and clinical characteristics of giant cell granuloma of the short bones of the hand and foot are similar to those of giant cell reparative granuloma, and it is difficult to distinguish between the two.
4. Treatment
Giant cell tumor of bone is a stage 3 or stage I tumor and should be treated surgically with surgical margins or greater than margins according to Enneking’s staging principles for tumors of the musculoskeletal system. The traditional standard of care for giant cell tumor is tumor debridement, using small pieces of autologous iliac bone containing cortical and cancellous bone to fill the cavity left by the debridement. Many practitioners still consider this autologous bone grafting method to be an acceptable standard of care. This intratumoral resection method only reaches the surgical border of the capsule, leaving small lesions within the bone.
No matter how careful and thorough the curettage is, some microscopic lesions may remain. The local recurrence rate of giant cell tumor can be as high as 40% to 60% with this method of scraping and bone grafting. Marginal or extensive resection of giant cell tumors is necessary. Complete resection reduces the recurrence rate of the tumor, but also poses some problems of defect repair and functional restoration. The ideal treatment should be a surgical approach of curettage with adjuvant therapy to achieve a marginal or wide excision, which reduces the recurrence rate of the tumor and preserves the function of the limb to a great extent.
Chemical or physical methods can help achieve this goal. Chemical methods such as phenol solution or anhydrous ethanol are applied to the surface within the tumor cavity after curettage; cytotoxic substances (e.g., chemotherapeutic agents that can be applied topically) are applied to the surface where local recurrence is likely to occur. Physical treatments include cryotherapy or heat therapy. Freezing of the cavity after tumor debridement is effective in controlling recurrence, but the incidence of postoperative local injury and bone complications is high.
Recurrence can be prevented by filling the remaining cavity within the tumor with heat generated by the bone cement, i.e., the thermogenic reaction of the bone cement causes local heating and necrosis of the remaining tumor tissue without damaging the normal tissue and causing complications. It is theoretically possible, but not reliable, that the cement produces local chemical cytotoxic effects during polymerization, and the main advantage of cement filling should be to allow early weight bearing and to facilitate observation of recurrence. The main advantage of cement filling should be to allow early weight bearing and to facilitate the observation of recurrence. The direction of treatment of giant cell tumor of bone should be to directly control the lesion without affecting the joint function.
A clear diagnosis before treatment of bone tumors is a fundamental prerequisite for appropriate treatment. After all imaging studies and preoperative preparation, biopsy should be performed. The biopsy should be performed by or under the direction of the physician preparing for surgical treatment. In most cases of giant cell tumor, puncture biopsy provides a definitive diagnosis and reduces the potential for local soft tissue contamination and implantation of tumor cells.
Another characteristic of giant cell tumors is the abundance of blood flow, and the use of a tourniquet is helpful for surgical treatment. Preoperative arterial embolization can be performed the day before or on the day of surgery for lesions that cannot be treated with a tourniquet but are rich in blood flow, using gelatin sponges or polyethylene ethanol balls selectively placed into the branches of the artery supplying the tumor, which can significantly reduce bleeding when the tumor is resected internally or marginally.
If extensive focal or marginal resection is the ideal approach, it is important to expose the normal cortical-lesion junction during surgery in order to confirm the migration of normal tissue to the pathological tissue. The characteristics of giant cell tumor of bone dictate that the mass is already very large before diagnosis, and care should be taken to contaminate the tumor by inadvertent entry during blunt separation due to its unclear margins. At any time before tumor resection, extra-articular resection should be considered in patients with tumor fractures or joint space contamination due to incisional biopsy.
If tumor cells may remain, the synovial membrane should be carefully examined and extensively resected. Giant cell tumors affecting the bony ends of long bones may result in loss of joint function and require joint reconstruction. Reconstruction with non-biologic materials, including artificial joints, is an option, but it is important to ensure that no tumor is present in the soft tissues or bone within the extensive area of insertion and implantation with the artificial joint. One method of filling the bone defects around the knee joint with biomaterials is arthrofusion, in which the tumor is removed and then fixed with an intramedullary nail to the end of the autogenous fibula, tibia and femur.
This method provides stability of the knee joint, but has the disadvantage of fusion of the knee joint. Reconstruction of the distal radius with a fibular autograft requires removal of both carpal bones, and the resulting carpal joint provides a functional upper extremity.
Most giant cell tumors of bone are treated by curettage with local adjuvant therapy. The choice of surgical incision is based on the local anatomy and the site of tumor destruction. The incisional exposure should include the reactive area and surrounding normal bone, which allows for windowing and removal of the lesion. It is undesirable and dangerous to scrape large lesions through a small bone window such as a bottle neck, and a full bone window should be opened to expose all intraosseous lesions to avoid incomplete scraping due to bone or soft tissue coverage.
For reconstruction after tumor debridement, the bone defect should be filled with a suitable material to restore the strength of the subchondral bone in as short a time as possible. If the lesion is small, autologous bone grafting can quickly solve the problem. The use of allograft bone to fill the bone defect is later than autologous bone to reconstruct the blood flow, and is considered by most to be the second best option. If the bone defect is too large for autologous bone to fill, a combination of autologous and allogeneic bone can be implanted. In this case, the autologous bone should be placed directly in the subchondral area of the joint, while the allograft bone should be placed in an area less important for bone repair.
The bone cement (methyl methacrylate) is instilled under a tourniquet, which allows it to function as a polymer in the absence of blood. The wound is closed layer by layer with absorbable thread, and a drainage tube is routinely placed deep along the long axis to the resection site, with an opening near the incision, and this tube is connected out of the body so that if the tumor recurs, the channel can be removed as well. If the patient does not show any recurrence after a period of recovery with bone cement, the cement can be replaced by subchondral bone implants and allograft bone.
Local or other recurrences at the access site after marginal resection or extended local resection can result from soft tissue contamination from resection or biopsy. The outcome of treatment of giant cell tumor of bone with marginal or extensive resection is related to the biology of the tumor; functional recovery after surgical treatment is related to the extent of resection and the method of reconstruction.
Complication rates are high in allogeneic bone graft cases, but acceptable function is achieved in approximately 3/4 of cases. The complications of distal radius autograft and joint fusion are similarly high, but satisfactory results are achieved in most cases. The results of intratumoral resection using a curettage approach are associated with significant local tumor recurrence. The complications of effective curettage with physical and chemical adjuvant therapy are mainly wound complications and fracture of the diseased bone.
With proper management, the results can still be satisfactory. Amputation is also an effective treatment for large, extensively invasive giant cell tumors of the limb that cannot be resected or effectively reconstructed within safe surgical borders.
Chemotherapy is unsatisfactory for giant cell tumors of the bone and should be chosen carefully. Patients with distant metastases, whether preoperative or postoperative, can be controlled with chemotherapy before resection of the metastases.
Radiation therapy for giant cell tumor of bone may lead to secondary sarcoma at the site of origin. A small number of benign giant cell tumors of bone with a clear diagnosis and primary or secondary lesions that cannot be surgically resected can be treated with high-voltage radiation therapy. For spinal giant cell tumors, intratumoral resection can be performed to maintain spinal stability, and the tumor can be removed with anterior biological reconstruction followed by low-dose radiation therapy to control the remaining microscopic lesions. For lesions that cannot be resected, vascular embolization can be performed.
Surgery is contraindicated for giant cell tumors of the sacrum and part of the spine, and radiotherapy is contraindicated for tumor malignancy. The results are usually seen by the 3rd or 4th month after embolization. After several years, the size of the tumor decreases to varying degrees, and calcifications can be seen in the center or at the edges of the tumor. If the tumor recurs, further embolization is required. Although arterial embolization is effective, not all patients are cured.
Embolization of spinal tumors carries the risk of nerve and spinal cord injury. Malignant giant cell tumor refers to a local recurrence of giant cell tumor of bone after several years of treatment, especially after radiation therapy, with clinical, imaging, and histologic manifestations of sarcoma. The main malignant transformation is osteogenic sarcoma, malignant fibrous histiocytoma or fibrosarcoma, which is treated in the same way as the primary malignant bone tumor.