Approach Considerations
The presence of tumor is the indication for surgery.
Radiation therapy and embolization [60] generally are reserved for cases in which surgical treatment is not feasible. Radiation therapy has been proposed for patients who are not surgical candidates, for those whose tumors are in locations not amenable to operative treatment, and for those in whom a potential for significant morbidity from tumor relapse or subsequent surgery exists. [61, 62]
Many authors reported a strong association between radiation therapy and malignant transformation of the giant cell tumor (GCT). [2, 6, 8, 63, 64, 65, 18] However, much of this information was derived during the era of orthovoltage radiation. Subsequent studies examined the effect of megavoltage radiation and showed it to be well tolerated and not associated with malignant transformation. GCTs that have undergone malignant transformation are treated as sarcomas. [66, 67, 61, 68, 62]
Although megavoltage radiation now is used, recommendations regarding radiation dose and fractionation schedules vary in the literature. Dose recommendations range from 35 to 70 Gy. [66, 67, 69, 61, 68] Recurrence rates in these series ranged from 10% to 15%, and malignant transformation was uncommon. However, long-term follow-up still is warranted.
Medical Therapy
In June 2013, the FDA approved denosumab for the treatment of unresectable GCT of bone (GCTB) in adults and skeletally mature adolescents. Approval was based on positive results from two open-label trials involving 305 patients with GCTB that was either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. [70, 71] Additional trials have found denosumab to be effective, though the recurrence rate remains a concern. [72, 73]
Pulmonary metastases have been cited as the cause of death in 16-25% of reported cases. [9, 21, 74] The need for early detection and treatment of these metastases has been emphasized. Pulmonary metastases have been treated with wide resection, chemotherapy, radiation therapy, and interferon alfa. When possible, wide surgical resection is the treatment of choice. [20, 8, 9, 21, 13]
When the pulmonary metastases cannot be completely surgically excised, adjuvant treatment, such as chemotherapy or radiation therapy, has been advocated. In addition, in situations when the metastases are unresectable, both chemotherapy and radiation have been used as solitary agents. [75, 76, 21, 77, 78, 79] At University of Texas MD Anderson Cancer Center, interferon has been used with promising results. [80]
Spontaneous malignant transformation of GCT is not uncommon. Malignant transformation has been defined as a sarcoma associated with a benign typical GCT at presentation or as a sarcoma arising at the site of a preexisting GCT. [18] Malignant transformations have resulted in osteosarcoma, fibrosarcoma, or malignant histiocytoma. [80, 81, 64] Periods of 4-40 years for malignant transformation have been reported. [81, 63, 64, 23] Cases of denosumab-related malignant transformation of benign GCT of bone have been reported. [82]
Surgical Therapy
In the past, GCTs were treated with amputation or with wide resection and reconstruction. However, with the knowledge that GCT is a locally aggressive yet benign disease, the surgical treatment of GCTs has become intralesional for most locations. [83] Joint-sparing approaches have been found to be feasible even for grade 2 and 3 GCTs of bone around the knee. [84]
Various treatment options have been advocated, including the following:
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Curettage
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Curettage and bone grafting
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Curettage and insertion of polymethylmethacrylate (PMMA) [85]
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Primary resection
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Radiation therapy
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Embolization of the feeding vessels (eg, for sacral and pelvic GCTs of bone that are not amenable to surgery [60] )
Resection
Although intralesional procedures remain the treatment of choice for most GCTs, wide en-bloc resection offers the lowest recurrence rate [86, 83] and can be performed in expandable bone. In the proximal fibula, wide resection without reconstruction is often performed. Similarly, GCTs of the distal radius often are resected and reconstructed with autograft or allograft (see the images below).
Intraoperative photograph of resection bed of same giant cell tumor of distal radius as in preceding image after distal radius is resected.
Intraoperative photograph of same giant cell tumor of distal radius as in previous two images shows wrist arthrodesis with fibular autograft and 16-hole low-contact dynamic compression (LCDC) plate.
Postoperative lateral radiograph of same giant cell tumor of distal radius as in preceding image.
However, in the long bones, resection necessitates prosthetic or allograft reconstruction and is generally reserved for grade 3 lesions. [87, 88, 89, 90]
Intralesional procedures
Intralesional curettage with bone grafting is a limb-sparing option that is associated with good functional and oncologic outcomes. However, simple curettage with or without bone grafting has recurrence rates of 27-55%. [6, 81, 8, 11, 12, 91] The high risk of recurrence led several surgeons to replace bone graft packing of the lesion with PMMA packing (see the images below). The heat given off by the hardening PMMA is thought to lead to thermal necrosis of the remaining tumor cells in the curetted cavity. [92, 93]
Giant cell tumor. Intraoperative photograph of distal tibia reveals curetted and burred cavity.
Giant cell tumor. Intraoperative photograph of same distal tibia as in preceding image reveals polymethylmethacrylate packed into distal tibial cavity.
The PMMA technique, compared with bone grafting, offers the advantages of lack of donor-site morbidity, an unlimited supply, immediate structural stability, low cost, and ease of use. In addition, the barium contained in the PMMA results in a radiopaque substance that sharply contrasts with the surrounding bone (see the image below). Local recurrences are more readily apparent than in cases where bone graft is used. [85]
Giant cell tumor. Anteroposterior radiograph of distal tibia with polymethylmethacrylate packed in distal femur after curettage of lesion.
The disadvantages of using cement include difficulty in removing it when revision is needed and the possibility that subchondral cement may predispose the joint to early degenerative osteoarthritis. [94, 95] The latter possibility has been debated. [96, 97, 98, 99] Using a canine model, Frassica et al found that subchondral PMMA did not in fact cause joint degeneration. However, in a later study, Frassica et al showed that subchondral bone grafts were superior to cement for restoration of the normal subchondral anatomy. [30]
Investigators have shown no differences in recurrence when comparing bone graft with PMMA. [100]
Several authors have added the technique of high-speed burring of the cavity after simple intralesional curettage. A large cortical window is necessary to expose the entire tumor and tumor cavity, allowing thorough curettage and burring of the cavity (see the first image below). This has been found to reduce the recurrence rates to 12-25%.
Giant cell tumor. Illustration of large cavity necessary for sufficient curettage.
The high-speed burr (see the second image below) not only adds a thermal component to eradication of the tumor but also allows more thorough removal of the tumor. High-speed burring of the cavity then may be followed by a chemical or physical adjuvant and packing of the lesion with PMMA or a bone graft. [101, 92]
Intraoperative photograph of distal femur after removal of giant cell tumor. Cavity has been curetted and treated with high-speed burr.
Adjuvant therapies
A review of the literature reveals that adjuvant treatment, when paired with intralesional curettage, offers excellent recurrence-free survival. Successful treatment of GCTs depends more on the thoroughness of intralesional curettage than on the specific adjuvant employed. The adequacy of tumor removal is influenced by tumor location, associated fracture, soft-tissue extension, and an understanding of the functional consequences of resection. The specific adjuvant treatment used appears to be at the surgeon's discretion; each option has advantages and disadvantages.
Although each of the various adjuvant therapies (eg, phenol, liquid nitrogen, or H2O2 and argon-beam coagulation) has advantages and disadvantages, [85] they all offer a method for eradication of microscopic disease. Many authors suggest that phenol is an effective means of decreasing the recurrence rate of GCTs. After curettage is performed and all perforations in the bone are sealed, phenol is poured into the cavity. This results in cellular death at a depth of approximately 1-2 mm. The use of 5% phenol has been advocated. [102, 103, 104, 105, 96, 74]
Recurrence rates with curettage and phenol and packing with PMMA or bone grafts are in the range of 5-17%. Phenol is systemically toxic. Preventing exposure to the surrounding tissues while at the same time allowing exposure to the entire curetted cavity is difficult. It can cause a serious chemical burn, and it is also readily absorbed through the skin and mucosa. The material has a hazardous effect on the nervous system, heart, kidneys, and liver. It damages the DNA, coagulates protein, and causes cellular necrosis. Several authors have raised concerns about the rapid absorption of phenol through cancellous bones. [102, 103, 104, 105, 96, 74]
Many authors have advocated cryosurgery as an adjuvant. Liquid nitrogen is a chemical reagent used in cryosurgery. In the direct-pour technique, after the curettage is performed and after all perforations in the bone are sealed, liquid nitrogen is poured through a stainless steel funnel into the cavity (see the image below). [106, 107, 108, 109, 110, 111]
The liquid nitrogen is left in the cavity until it all evaporates. The surrounding tissues are irrigated with warm sodium chloride solution in an attempt to prevent or minimize thermal injury to the surrounding tissues. The process is repeated two or three times, resulting in cellular death at a depth of approximately 1-2 cm. The cavitary defect is then reconstructed with PMMA or bone grafts. [112]
Recurrence rates with cryosurgery have been reported to be in the range of 2-12%. The disadvantages of cryosurgery include the need for wide exposure, the need to protect the soft tissues, skin necrosis, osteonecrosis, and fracture. Fracture is the most commonly reported and gravest complication. [106, 101, 107, 108, 109, 110, 111]
Malawer et al noted that internal fixation with Steinmann pins and reconstruction of the cavitary defect with PMMA significantly reduced the incidence of fracture and suggested that all patients who undergo cryosurgery receive internal stabilization as well (see the images below). [107]
Intraoperative photograph of distal femur with polymethylmethacrylate and Steinman pins inserted into cavity after removal of giant cell tumor.
Lateral radiograph of same distal femur as in preceding image with polymethylmethacrylate and Steinman pins inserted into cavity after removal of giant cell tumor.
Some authors, as an alternative to cryosurgery and phenol therapy, have advocated argon-beam coagulation. This modality lacks the application hazards identified with both phenol and liquid nitrogen. Thermal coagulation applied through a concentrated argon gas is used to paint the tumor cavity (see the images below). [113]
Giant cell tumor. Intraoperative photograph of distal femoral cavity of same distal femur as in preceding image, obtained while cavity is undergoing argon laser treatment.
Giant cell tumor. Intraoperative photograph of distal femoral cavity of same distal femur as in preceding image, obtained after argon laser treatment is complete.
The penetration is approximately 2-3 mm. Reported recurrence rates for this procedure when paired with PMMA are approximately 7%. No acute complications were noted. Long-term follow-up is warranted to assess the effect of argon-beam coagulation on joint and/or subchondral physiology and on the incidence of pathologic fracture.
Some studies have suggested that zoledronic acid supplementation may reduce the incidence of tumor recurrence after surgical treatment of GCT of bone; further study is warranted. [114]
There is some experimental evidence to suggest that melatonin might prove to be a useful therapeutic adjunct. A study by Wang et al, using human cells and nude mice, found that melatonin was capable of inhibiting the proliferation, migration, and invasion of GCT of bone cells and of promoting the apoptosis and osteogenic differentiation of tumor cells. When melatonin was combined with zoledronic acid, a stronger antitumor effect was observed. [115]
Complications
Complications are frequent after surgical treatment of GCTs of bone, in many cases necessitating revision surgery. In a single-center retrospective study of 192 patients undergoing initial surgical treatment of GCT of bone surgery (curettage, n = 152; resection, n = 40), Barnaba et al reported that 171 revision procedures were required in 92 patients. [116] Of these 171 procedures, 43 were done for mechanical reasons, 30 for infection, 86 for tumor recurrence, and 12 for other causes. At 10 years, the cumulative incidence of revision was 36% for recurrence, 26% for mechanical causes, and 13% for infection.
Long-Term Monitoring
After treatment, patients with GCT should be monitored with serial physical examinations and radiography of the involved site and of the chest. Relapses may be associated with new pain or swelling. Tumor recurrences have been noted many years after initial treatment, and long-term observation of at least 5 years is recommended. [117] The presence of secondary aneurysmal bone cysts may be a risk factor for postoperative recurrence. [118]
A study by Rosdario et al recommended intensified surveillance (preferably with CT) for pulmonary metastases in patients with local recurrence of GCT of bone patients with LR, especially for 3 years from the diagnosis of local recurrence. [25]
In summary, GCTs of bone are benign but locally aggressive primary bone tumors. Local control is most closely related to complete tumor removal. However, the functional consequences and good long-term results often dictate intralesional (curettage) procedures.
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Approximately 50% of giant cell tumors are located around knee. Most common locations are distal femur, proximal tibia, and proximal humerus and distal radius.
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Distribution of giant cell tumors according to age and sex of patient. Six patients had multicentric disease.
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Giant cell tumor. Anteroposterior radiograph of distal femur reveals expansile lytic metaphyseal-epiphyseal lesion.
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Giant cell tumor. Lateral radiograph of same distal femur as in previous image reveals expansile lytic metaphyseal-epiphyseal lesion.
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Giant cell tumor. Anteroposterior radiograph of distal radius reveals aggressive lesion characterized by extensive local bony destruction, cortical breakthrough, and significant soft-tissue expansion.
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Giant cell tumor. Lateral radiograph of same distal radius as in previous image reveals aggressive lesion characterized by extensive local bony destruction, cortical breakthrough, and significant soft-tissue expansion.
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Giant cell tumor. Sagittal MRI of same distal radius as in previous two images reveals aggressive lesion characterized by extensive local bony destruction, cortical breakthrough, and significant soft-tissue expansion.
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Giant cell tumor. Anteroposterior radiograph of distal tibia demonstrates extension of lesion to articular surface.
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Giant cell tumor. Lateral radiograph of same distal tibia as in preceding image demonstrates extension of lesion to articular surface.
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Giant cell tumor. Sagittal MRI of same distal tibia as in previous two images demonstrates extension of lesion to articular surface.
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Anteroposterior radiograph of wrist arthrodesis performed for giant cell tumor. Soft-tissue recurrence is present. Note peripheral mineralization about soft-tissue recurrence (arrow).
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Sagittal T1-weighted MRI shows giant cell tumor with low signal intensity.
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Sagittal T2-weighted MRI shows giant cell tumor with intermediate-to-high signal intensity.
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Giant cell tumor. CT scan of distal femur reveals absence of matrix within lesion.
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Intraoperative photograph of giant cell tumor in distal femur.
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Gross specimen of same giant cell tumor in the distal femur as in preceding image displays typical chocolate-brown and spongy appearance.
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Bisected gross specimen of giant cell tumor in preceding image reveals blood-filled cystic areas and inner yellow and orange discoloration.
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Gross specimen of giant cell tumor that fills entire distal radius. Despite cortical disruption, periosteum remains intact (arrow). Once again, note blood-filled cystic areas and areas of orange discoloration.
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Photomicrograph of giant cell tumor reveals typical appearance. Multinucleated giant cells are dispersed throughout on background of mononuclear cells.
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Photomicrograph of giant cell tumor reveals typical appearance. Multinucleated giant cells are dispersed throughout on background of mononuclear cells.
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Photomicrograph of giant cell tumor reveals prominent mitotic activity and rare cellular atypia.
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Photomicrograph of giant cell tumor reveals prominent mitotic activity and rare cellular atypia.
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Giant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.
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Giant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.
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Giant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.
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Photomicrograph of giant cell tumor with few multinucleated giant cells but abundant swirls of spindle-shaped stromal cells.
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Photomicrograph of giant cell tumor with few multinucleated giant cells but abundant swirls of spindle-shaped stromal cells.
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Photomicrograph of giant cell tumor with intravascular invasion of multinucleated giant cells.
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Anteroposterior radiograph of giant cell tumor of distal radius.
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Intraoperative photograph of resection bed of same giant cell tumor of distal radius as in preceding image after distal radius is resected.
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Intraoperative photograph of same giant cell tumor of distal radius as in previous two images shows wrist arthrodesis with fibular autograft and 16-hole low-contact dynamic compression (LCDC) plate.
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Postoperative lateral radiograph of same giant cell tumor of distal radius as in preceding image.
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Giant cell tumor. Intraoperative photograph of distal tibia reveals curetted and burred cavity.
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Giant cell tumor. Intraoperative photograph of same distal tibia as in preceding image reveals polymethylmethacrylate packed into distal tibial cavity.
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Giant cell tumor. Anteroposterior radiograph of distal tibia with polymethylmethacrylate packed in distal femur after curettage of lesion.
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Giant cell tumor. Illustration of large cavity necessary for sufficient curettage.
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Giant cell tumor. Illustration of direct pour technique.
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Intraoperative photograph of distal femur with polymethylmethacrylate and Steinman pins inserted into cavity after removal of giant cell tumor.
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Lateral radiograph of same distal femur as in preceding image with polymethylmethacrylate and Steinman pins inserted into cavity after removal of giant cell tumor.
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Intraoperative photograph of distal femur after removal of giant cell tumor. Cavity has been curetted and treated with high-speed burr.
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Giant cell tumor. Intraoperative photograph of distal femoral cavity of same distal femur as in preceding image, obtained while cavity is undergoing argon laser treatment.
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Giant cell tumor. Intraoperative photograph of distal femoral cavity of same distal femur as in preceding image, obtained after argon laser treatment is complete.
