Giant Cell Tumor of Bone Treatment & Management


Practice Essentials

First described by Cooper and Travers in 1818, [1 giant cell tumors (GCTs) of bone have been labeled the most challenging benign bone tumors. [2 Although benign, GCTs show a tendency for significant bone destruction, local recurrence, and occasionally metastasis. The natural history of GCTs varies widely and can range from local bony destruction to local metastasis, metastasis to the lung, metastasis to lymph nodes (rare), or malignant transformation (rare). [3456789101112132141516171819]

A low percentage (1-9%) of GCTs of bone metastasize to the lung. [20 The metastases appear as clusters of GCTs located within the lung. [2152223GCT metastases generally appear an average of 3-5 years after the initial diagnosis of the primary lesion; however, in some cases, they may go undetected for 10 years or longer. [102224232526 The natural history of these lung metastases is unpredictable. Pulmonary metastases that spontaneously regress, remain stable, continuously grow slowly, or rapidly progress have been reported. [21410142728]

Pain is the most common presenting symptom. Swelling and deformity are associated with larger lesions. Soft-tissue extension is common. The incidence of pathologic fracture at presentation is 11-37%.

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. 

Epidemiology

In the United States and Europe, GCTs represent approximately 5% of all primary bone tumors and 21% of all benign bone tumors. [19In China, GCTs account for 20% of all primary bone tumors. [29 An epidemiologic comparison study between 9200 patients treated at Beijing Ji Shui Tan Hospital and 10,165 patients treated at the Mayo Clinic found that the incidence of GCT was significantly higher among the former. [30]

A female predominance exists, with a female-to-male ratio of 1.3-1.5:1 (see the image below). [313219GCTs occur most commonly in the third decade of life; fewer than 5% of GCTs occur in patients who are skeletally immature. [319333435In the Mayo Clinic series, 84% of the GCTs occurred in patients older than 19 years. [19]

Distribution of giant cell tumors according to ageDistribution of giant cell tumors according to age and sex of patient. Six patients had multicentric disease.

Prognosis

The overall prognosis generally is good. However, pulmonary metastases have been cited as the cause of death in 16-25% of reported cases. [102224]

In a study comparing the outcomes of two surgical treatments—curettage (n = 14) and segmental resection (n = 13)—in patients with GCTs of the proximal humerus who were followed for more than 2 years, Bai et al found that the recurrence rate was 7.1% in the curettage group and 15.4% in the segmental resection group. [36 Postoperative upper-extremity function was significantly better in the curettage group than in the segmental resection group.



History and Physical Examination

Most giant cell tumors (GCTs) of bone are located within the epiphyses of long bones, but they often extend into the metaphysis. In several published series, only 1.2% of GCTs involved the metaphysis or diaphysis without epiphyseal involvement. [3738394041424344]

Approximately 50% of GCTs are located around the knee. The most common locations are the distal femur, the proximal tibia, and the proximal humerus and distal radius (see the image below). Most commonly, GCTs are solitary lesions; fewer than 1% are multicentric. [4546474849505152Multicentric involvement tends to be more clinically aggressive, and, unlike the solitary lesions, multicentric GCT has a propensity for the small bones of the hands and feet. Patients with multicentric lesions tend to be younger than those with lesions elsewhere. [53]

Approximately 50% of giant cell tumors are locatedApproximately 50% of giant cell tumors are located around knee. Most common locations are distal femur, proximal tibia, and proximal humerus and distal radius.

Pain is the most common presenting symptom. Swelling and deformity are associated with larger lesions. Soft-tissue extension is common. The incidence of pathologic fracture at presentation is 11-37%.



Radiography

Radiographically, giant cell tumors (GCTs) are lucent and eccentrically located within the bone. These lesions can appear aggressive and are often characterized by extensive local bony destruction, cortical breakthrough, and soft-tissue expansion (see the images below).

Giant cell tumor. Anteroposterior radiograph of diGiant cell tumor. Anteroposterior radiograph of distal femur reveals expansile lytic metaphyseal-epiphyseal lesion.
Giant cell tumor. Lateral radiograph of same distaGiant cell tumor. Lateral radiograph of same distal femur as in previous image reveals expansile lytic metaphyseal-epiphyseal lesion.
Giant cell tumor. Anteroposterior radiograph of diGiant cell tumor. Anteroposterior radiograph of distal radius reveals aggressive lesion characterized by extensive local bony destruction, cortical breakthrough, and significant soft-tissue expansion.
Giant cell tumor. Lateral radiograph of same distaGiant 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.

When located in the epiphysis, GCTs generally extend to the articular surface (see the images below).

Giant cell tumor. Anteroposterior radiograph of diGiant cell tumor. Anteroposterior radiograph of distal tibia demonstrates extension of lesion to articular surface.
Giant cell tumor. Lateral radiograph of same distaGiant cell tumor. Lateral radiograph of same distal tibia as in preceding image demonstrates extension of lesion to articular surface.

Although radiographs of GCTs demonstrate a narrow zone of transition, GCTs generally lack the dense peripheral sclerosis seen in nonossifying fibromas. Mineralization of the primary lesion is rare. However, when GCTs occur in the soft tissue (metastasis or local recurrence), peripheral calcifications are common (see the image below).

Anteroposterior radiograph of wrist arthrodesis peAnteroposterior radiograph of wrist arthrodesis performed for giant cell tumor. Soft-tissue recurrence is present. Note peripheral mineralization about soft-tissue recurrence (arrow).

Campanacci et al proposed a grading system for GCTs that was based on the radiographic appearance of the tumors. [38 The Campanacci grading system is similar to that proposed by Enneking for benign bone tumors. [54]

  • A grade 1 lesion (latent) has a well-defined margin and an intact cortex
  • A grade 2 lesion (active) has a relatively well-defined margin but no radiopaque rim, and the cortex is thinned and moderately expanded
  • A grade 3 lesion (aggressive) has indistinct borders and cortical destruction) [338]
  • No correlation exists between the grading systems and the incidence of local recurrence or metastases

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) often is performed to delineate the extent of the neoplasm. In the typical GCT, the signal intensity is homogeneous, and the lesion is well circumscribed. The lesions have low signal intensity on T1-weighted images and intermediate signal intensity on T2-weighted images (see the images below).

Sagittal T1-weighted MRI shows giant cell tumor wiSagittal T1-weighted MRI shows giant cell tumor with low signal intensity.
Sagittal T2-weighted MRI shows giant cell tumor wiSagittal T2-weighted MRI shows giant cell tumor with intermediate-to-high signal intensity.
Giant cell tumor. Sagittal MRI of same distal radiGiant 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.
Giant cell tumor. Sagittal MRI of same distal tibiGiant cell tumor. Sagittal MRI of same distal tibia as in previous two images demonstrates extension of lesion to articular surface.

Computed Tomography

Computed tomography (CT) scans of the lesion reveal an absence of bone and intralesional mineralization (see the image below).

Giant cell tumor. CT scan of distal femur reveals Giant cell tumor. CT scan of distal femur reveals absence of matrix within lesion.

Histologic Findings

On gross inspection, these lesions are characteristically chocolate brown, soft, spongy, and friable (see the image below).

Gross specimen of  same giant cell tumor in the diGross specimen of same giant cell tumor in the distal femur as in preceding image displays typical chocolate-brown and spongy appearance.

Yellowish-to-orange discoloration due to hemosiderin may be present. Cystic cavities within the tumor are common. Often, these cavities are blood-filled (see the image below).

Bisected gross specimen of giant cell tumor in preBisected gross specimen of giant cell tumor in preceding image reveals blood-filled cystic areas and inner yellow and orange discoloration.

Examination of the resected specimen reveals a variable degree of cortical expansion and disruption. Despite the cortical disruption, the periosteum remains intact (see the image below). [19]

Gross specimen of giant cell tumor that fills entiGross 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.

Histologically, the lesions tend to be cellular. Although the multinucleated giant cell is the characteristic cell type, these lesions have a background network of stromal mononuclear cells (see the images below).

Photomicrograph of giant cell tumor reveals typicaPhotomicrograph of giant cell tumor reveals typical appearance. Multinucleated giant cells are dispersed throughout on background of mononuclear cells.
Photomicrograph of giant cell tumor reveals typicaPhotomicrograph of giant cell tumor reveals typical appearance. Multinucleated giant cells are dispersed throughout on background of mononuclear cells.

The mononuclear cells are plump and round, oval, or spindle-shaped. They may have prominent mitotic activity, but cellular atypia is rare (see the images below). The degree of mitotic activity has no prognostic significance.

Photomicrograph of giant cell tumor reveals prominPhotomicrograph of giant cell tumor reveals prominent mitotic activity and rare cellular atypia.
Photomicrograph of giant cell tumor reveals prominPhotomicrograph of giant cell tumor reveals prominent mitotic activity and rare cellular atypia.

Multinucleated giant cells, as the name suggests, have numerous centrally located nuclei as opposed to the peripherally located nuclei of Langerhans-type giant cells seen in atypical infections (see the images below). The nuclei tend to be compact and oval and contain prominent nucleoli. These are similar in appearance to those of the surrounding stromal cells, and the giant cell often appears to be a syncytium of these stromal cells. [5657]

Giant cell tumor. Photomicrograph of multinucleateGiant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.
Giant cell tumor. Photomicrograph of multinucleateGiant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.
Giant cell tumor. Photomicrograph of multinucleateGiant cell tumor. Photomicrograph of multinucleated giant cell. Note centrally located nuclei.

Giant cells generally are distributed throughout the lesion. The concentration of multinucleated giant cells varies considerably from tumor to tumor. Some tumors have many multinucleated giant cells, whereas others have a few giant cells nestled in swirls of spindle-shaped stromal cells (see the images below).

Photomicrograph of giant cell tumor with few multiPhotomicrograph of giant cell tumor with few multinucleated giant cells but abundant swirls of spindle-shaped stromal cells.
Photomicrograph of giant cell tumor with few multiPhotomicrograph of giant cell tumor with few multinucleated giant cells but abundant swirls of spindle-shaped stromal cells.

The concentration of multinucleated giant cells is not related to the incidence of local recurrence or metastases. In some lesions, giant cells invade the small perforating vessels (see the image below). This intravascular invasion can be found in approximately 5% of cases. This invasion, although appearing aggressive, is not correlated with the prognosis. [28]

Photomicrograph of giant cell tumor with intravascPhotomicrograph of giant cell tumor with intravascular invasion of multinucleated giant cells.

At histologic analysis, the differential diagnosis includes brown tumors of hyperparathyroidismaneurysmal bone cysts; and, rarely, chondroblastomaosteoblastoma, or osteosarcoma.

In an attempt to relate the histologic features with the clinical course, several histologic grading systems have been developed. The earliest was devised by Jaffe et al in 1940 and comprised three grades, as follows:

  • In grade I, at the benign end of the spectrum, giant cells are numerous, mononuclear cells are rare, and mitotic activity is absent
  • In grade II, mononuclear stromal cells are numerous, and moderate atypia and mitotic activity is seen
  • In grade III, giant cells are few and small, atypia and pleomorphism are common, and mitotic activity is frequent

However, this grading system has no prognostic significance. [358959In an attempt to improve the prognostic relevance of the histologic grading system, several authors have modified the staging system of Jaffe et al. [28Generally, these staging systems include sarcomatous lesions as grade III lesions. Unfortunately, these modified systems, like that of Jaffe et al, are of little value in predicting patient outcomes.


Approach Considerations

The presence of tumor is the indication for surgery.

Radiation therapy and embolization [60generally 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. [6162]

Many authors reported a strong association between radiation therapy and malignant transformation of the giant cell tumor (GCT). [37963646519However, 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. [6667616862]

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. [6667696168Recurrence 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. [7071 Additional trials have found denosumab to be effective, though the recurrence rate remains a concern. [7273]

Pulmonary metastases have been cited as the cause of death in 16-25% of reported cases. [102274The 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. [219102214]

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. [757622777879At 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. [19Malignant transformations have resulted in osteosarcomafibrosarcoma, or malignant histiocytoma. [808164Periods of 4-40 years for malignant transformation have been reported. [81636424Cases 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]

Various treatment options have been advocated, including the following:

  • Curettage
  • Curettage and bone grafting
  • Curettage and insertion of polymethylmethacrylate (PMMA) [84]
  • Primary resection
  • Radiation therapy
  • 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 [8583and 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).

Anteroposterior radiograph of giant cell tumor of Anteroposterior radiograph of giant cell tumor of distal radius.
Intraoperative photograph of resection bed of sameIntraoperative 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 tumorIntraoperative 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 celPostoperative 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. [86878889]

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%. [7819121390The 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. [9192]

Giant cell tumor. Intraoperative photograph of disGiant cell tumor. Intraoperative photograph of distal tibia reveals curetted and burred cavity.
Giant cell tumor. Intraoperative photograph of samGiant 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. [84]

Giant cell tumor. Anteroposterior radiograph of diGiant 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. [9394The latter is a theory that remains to be proved. [95969798Using 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. [31]

Investigators have shown no differences in recurrence when comparing bone graft with PMMA. [99]

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 necGiant 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. [10091]

Intraoperative photograph of distal femur after reIntraoperative 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, [84 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. [1011021031049574]

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. [1011021031049574]

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). [105106107108109110]

Giant cell tumor. Illustration of direct pour techGiant cell tumor. Illustration of direct pour technique.

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. [111]

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. [105100106107108109110]

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). [106]

Intraoperative photograph of distal femur with polIntraoperative 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 precLateral 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). [112]

Giant cell tumor. Intraoperative photograph of disGiant 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 disGiant 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.

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. [113 The presence of secondary aneurysmal bone cysts may be a risk factor for postoperative recurrence. [114]

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. [26]

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.


0 comments:

Post a Comment