Giant Cell Tumor Treatment & Management
- Author: Valerae O Lewis, MD; Chief Editor: Harris Gellman, MD more...
The presence of tumor is the indication for surgery.
Radiation therapy and embolization 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.[57, 58]
Many authors have reported a strong association between radiation therapy and malignant transformation of the giant cell tumor (GCT).[3, 7, 9, 59, 60, 61, 19] However, much of this information was derived during the era of orthovoltage radiation. Subsequent studies have examined the effect of megavoltage radiation and have shown it to be well tolerated and not associated with malignant transformation. GCTs that have undergone malignant transformation are treated as sarcomas.[62, 63, 57, 64, 58]
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.[62, 63, 65, 57, 64] Recurrence rates in these series ranged from 10-15%, and malignant transformation was uncommon. However, long-term follow-up still is warranted.
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. Of the 187 patients with measurable tumors, 47 experienced a reduction in tumor size after 3 months of treatment with the drug. Of these patients with an objective response, 24 (51%) had a duration of response lasting at least 8 months.[66, 67]
Pulmonary metastases have been cited as the cause of death in 16-25% of reported cases.[10, 21, 68] 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, 9, 10, 21, 14]
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.[69, 70, 21, 71, 72, 73] At University of Texas MD Anderson Cancer Center, interferon has been used with promising results.
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. Malignant transformations have resulted in osteosarcoma, fibrosarcoma, or malignant histiocytoma.[74, 75, 60] Periods of 4-40 years for malignant transformation have been reported.[75, 59, 60, 23]
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 is intralesional for most locations.
Various treatment options have been advocated, including the following:
Curettage and bone grafting
Curettage and insertion of polymethylmethacrylate (PMMA) 
Embolization of the feeding vessels
Although intralesional procedures remain the treatment of choice for most GCTs, wide en-bloc resection offers the lowest recurrence rate 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).
However, in the long bones, resection necessitates prosthetic or allograft reconstruction and is generally reserved for grade III lesions.[78, 79, 80, 81]
Intralesional curettage and 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%.[7, 75, 9, 12, 13, 82] 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.[83, 84]
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 methylmethacrylate 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 in which bone graft is used.
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.[85, 86] The latter is a theory that remains to be proved.[87, 88, 89, 90] In fact, using a canine model, Frassica et al showed that subchondral PMMA did not cause joint degeneration. However, in a later study, Frassica et al showed that subchondral bone grafts are superior to cement for restoration of the normal subchondral anatomy.
Investigators have shown no differences in recurrence when comparing bone graft with PMMA.
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%. 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.[92, 83]
Adjuvant therapies, such as phenol, liquid nitrogen, or H2O2 and argon beam coagulation, all have advantages and disadvantages. However, 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 a cellular death at a depth of approximately 1-2 mm. The use of 5% phenol has been advocated.[93, 94, 95, 96, 87, 68]
Recurrence rates with curettage and phenol and packing with PMMA or bone grafts are 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 the concern of the rapid absorption of the phenol through cancellous bones.[93, 94, 95, 96, 87, 68]
Many authors advocate 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).[97, 98, 99, 100, 101, 102]
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.
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.[97, 92, 98, 99, 100, 101, 102]
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).
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).
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.
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.
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.
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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