Treatment of giant cell tumor of bone: Current concepts

Giant cell tumor (GCT) of bone though one of the commonest bone tumors encountered by an orthopedic continues to intrigue treating surgeons. Usually benign, they are locally aggressive and may occasionally undergo malignant transformation. The surgeon needs to strike a balance during treatment between reducing the incidence of local recurrence while preserving maximal function. Differing opinions pertaining to the use of adjuvants for extension of curettage, the relative role of bone graft or cement to pack the defect and the management of recurrent lesions are some of the issues that offer topics for eternal debate. Current literature suggests that intralesional curettage strikes the best balance between controlling disease and preserving optimum function in the majority of the cases though there may be occasions where the extent of the disease mandates resection to ensure adequate disease clearance. An accompanying treatment algorithm helps outline the management strategy in GCT.

G iant cell tumor (GCT) of bone is one of the TREATMENT commonest benign bone tumors encountered by an orthopedic surgeon. The reported incidence of The treatment of GCT is directed towards local control GCT in the Oriental and Asian population is higher than without sacrificing joint function. This has traditionally that in the Caucasian population and may account for 20% been achieved by intralesional curettage with autograft of all skeletal neoplasms. 1,2 It has a well-known propensity reconstruction by packing the cavity of the excised tumor for local recurrence after surgical treatment.
with morsellised iliac cortico-cancellous bone. Regardless of how thoroughly performed, intralesional excision leaves Current recurrence rates between 10-20% with meticulous microscopic disease in the bone and hence has a reported curettage and extension of tumor removal using mechanized recurrence rate as high as 60%. 3 Although a marginal or wide burrs and adjuvant therapy are a vast improvement on excision of the involved bone is curative if contamination is the historically reported recurrence rates of 50-60% with avoided, it is associated with reconstruction and disability curettage alone.
problems. In order to counter the above problems, a great deal of effort has been expended on attempting to Certain controversies in the treatment of GCT continue "extend" the curettage or intralesional excision by chemical to intrigue treating surgeons. Do adjuvants like phenol or or physical means. cryotherapy for extension of curettage have any benefit; is it better to pack the defect with bone graft or cement; should Intralesional curettage a recurrent lesion be curetted again or widely excised; does one contemplate joint salvage or resection especially in large GCTs? These are some of the issues that offer topics for eternal debate.
This article endeavors to outline the principles of management of giant cell tumor of bone and addresses current opinion regarding some of these dilemmas. The key to ensuring an adequate curettage with complete removal of tumor is obtaining adequate exposure of the lesion. This is achieved by making a large cortical window to access the tumor so as to avoid having to curette under overhanging shelves or ridges of bone. Use of a head lamp and dental mirror combined with multiple angled curettes helps to identify and access small pockets of residual disease which may otherwise result in recurrence. A high power burr to break the bony ridges helps extend the curettage and is recommended. A pulsatile jet lavage system used at the end of the curettage helps to bare raw cancellous bone and physically wash out tumor cells.  • Immediate structural support and rapid weight-bearing Even pathological fractures through a giant cell tumor ambulation are not a contraindication to treatment by curettage and cementation. 10,11 Cryosurgery using liquid nitrogen first

Drawbacks of cementing
propagated by Marcove, though used in some centers, is • Not a biological material. Cement though strong in associated with a high incidence of local wound and bone compression is relatively weak when subjected to complications. 12, 13 shear and torsional forces. Hence its use in lesions involving the head and neck of the femur may result Do These Adjuvants Help?
in an increased chance of fractures through cement. Some recent studies though, have questioned the role of • Fear about long-term degeneration of articular cartilage adjuvants and filling agents in reducing the recurrence rate in subchondral lesions in weight-bearing areas of giant cell tumors. Adequate removal of the tumor seems to be a more important predictive factor for the outcome Recent studies have demonstrated the efficacy of bone of surgery than the use of adjuvants. The study by Trieb substitutes like calcium phosphate as a filling agent. 16 et al demonstrated that local recurrence rate of giant cell the patient is treated by cementation, there is a belief that tumors located in long bones treated with or without phenol it is necessary to remove the cement after an appropriate is similar. [14] Prosser et al retrospectively reviewed 193 passage of time (to be reasonably certain that local relapse patients treated during a 27-year period and compared their is not going to develop). The defect is subsequently results with historic controls. One hundred and thirty-seven reconstructed with autograft on the subchondral portion patients had curettage as a primary treatment and of these, of the repair supplemented with allograft to prevent late • 26 (19%) had local recurrences. The local recurrence rate articular degeneration. However, studies have shown that of giant cell tumors confined to bone (Campanacci Grades joint function is not compromised in time even after the use I and II) was only 7% compared with 29% in tumors with of subchondral cement. 17,18 There is an interesting report If extraosseous extension (Campanacci Grade III). They recommended primary curettage for intraosseous giant cell tumors without adjuvant treatment or filling agents, but tumors with soft tissue extension or with local recurrence may require more aggressive treatment. 15

Reconstructing the residual defect
Reconstructing the defect after curettage can be quite challenging. In case the gap left behind after the curettage is small and does not jeopardize the structural integrity of the bone it can be left alone and the cavities fill up with blood clot which then gets ossified to form bone. 15 For larger on two cases by Tejwani et al, both with symptomatic full-thickness tibial articular cartilage loss and one with a meniscal tear, after curettage, phenol cautery and PMMA reconstruction of giant cell tumor of the proximal tibia. Arthroscopic chondroplasty and planing of the exposed cement was performed in both cases, theoretically reducing focal areas of stress concentration that could lead to further meniscal damage and injury to the femoral condyle articular surface in weight-bearing. 19 To try and forestall this potential problem of late articular degeneration in subarticular lesions where the amount of residual subchondral bone after an extended curettage is less than 5 mm, a multilayer reconstruction technique is recommended. A mixture of morsellized auto and allograft (about 5-8 mm thick) is packed adjacent to the subarticular surface. A layer of gelfoam is layered over this and the remaining cavity is packed with cement [ Figure 2]. This helps reduce heat damage from the curing cement, and Gelfoam Cement the subarticular bone graft after consolidation should theoretically prevent articular degeneration. 20 Another perceived advantage is that should recurrence occur, the danger of damage to articular cartilage during removal of cement is reduced [ Figure 3].
Occasionally, Steinmann pins have been used to reinforce the bone cement used to fill the large subchondral defects following intralesional curettage. However, whether this is of real benefit in improving the stability of the defect is controversial. 21 Large lesions can cause weakening of the structural stability of bone. Depending on the residual structural integrity of the host bone it may be necessary to augment the construct with internal fixation.

Wide resection and subsequent reconstruction
In a study of 38 patients with giant cell tumor in the knee region Chen et al measured the area of affected subchondral bone radiographically using plain radiographs, CT and MRI and correlated it with the mean Enneking functional score at follow-up. In patients initially treated with curettage and bone grafting, the mean area of initially affected subchondral bone was 18.6% with a linear trend showing that the larger the area of affected subchondral bone, the worse the functional score. Among patients initially treated with wide resection, the mean area of affected subchondral bone was 68.2%. 20 Thus occasionally, even in benign tumors, resection may be the preferred option when bone salvagibility by intralesional methods would result in such

Lower end radius lesions
There is some debate regarding the management of GCT in the lower end radius. Some authors have reported a high rate of local recurrence in GCT of the distal radius and recommend that they should be treated more aggressively. Today the consensus of opinion would state that curettage should be attempted for the majority of patients with severe mechanical compromise that skeletal integrity is unlikely to be maintained or unlikely to be restored after healing, leading to a compromise in ultimate function 21 [ Figure 4]. In certain bones like the lower end ulna, upper end fibula etc. excision may be attempted as the treatment If marginal / wide local excision is elected as the treatment of the lesion, either primarily or in recurrence, then reconstruction necessarily implies reconstruction of the joint surface, since GCT invariably involves the end of a long bone and causes significant dysfunction of the joint surface. 22,23

The options include
Megaprosthetic joint replacement: These afford stability and mobility, however, are prone to ultimate loosening, wear or breakage and require revisions. Biologic reconstruction: These are technically demanding, but durable procedures affording stability at the cost of mobility. They include: • autograft arthrodesis (knee, wrist, shoulder) with internal / external fixation 24 • live microvascular fibula reconstructions (e.g., around knee and shoulder, distal radius reconstruction, distal fibula GCT with ankle reconstruction) 25-27 • Ilizarov method of bone regeneration 28,29 GCT of the distal radius [ Figure 5] but some form of stabilization may be required in the presence of extensive bone destruction. 32 Cheng et al. state that intralesional excision should not be excluded as a possible treatment of even Grade III lesions. They recommend Grade III lesions be treated with curettage when the tumor does not invade the wrist, destroy more than 50% of the cortex or break through the cortex with an extraosseous mass in more than one plane. 31

LOCAL RECURRENCE IN GCT
Local recurrences appear to be related to the surgical margin and are clinically characterized by pain and radiologically IJO -April -June 2007 / Volume 41 / Issue 2 by progressive lysis of the bone graft or the adjacent cancellous bone. Following curettage and cementation an osteolytic zone caused by thermal injury measuring 2 mm surrounds the cement. This radiolucent zone is bordered by a thin outer sclerotic rim for about six months. Lysis or failed development of the sclerotic rim between the cement and cancellous bone may suggest recurrence. 33

CHEMOTHERAPY AND RADIOTHERAPY
Occasional GCT of bone demonstrate profound responses to chemotherapy but these cases are anecdotal and their incidence is disappointing. At the present time there are no recognized effective chemotherapeutic agents available for the management of these tumors. The literature documents a close association of secondary sarcomatous transformation in the region of GCTs treated by radiation therapy. Though surgery remains the treatment of choice, (TACP) could be used as a tumor marker for monitoring radiotherapy is recommended when complete excision response to the treatment of GCT. Total serum acid or curettage is impractical for medical or functional phosphatase level in GCT patients correlated with tumor reasons (generally for lesions of the spine and sacrum) or size. The high preoperative TACP values in GCT patients for aggressive, multiply recurrent tumors. [39][40][41][42] In lesions became normalized after surgery but reappeared in three involving the axial skeleton, with the exception of the of five patients with local recurrence. 34 sacrum, excision with stabilization of the spine and biologic reconstruction of the anterior column 43 Though the majority of recurrences usually occur within the reduced levels of irradiation (45 Gy in 4.5 weeks), on the first two years, late recurrences are known and long-term assumption that you are dealing with microscopic residual surveillance is recommended in these patients. 35,36 Even tumor only, would offer the patient the best chance of though the increasing grade from I to III is not a reflection long-term local control. The use of modern-day techniques of the biologic aggressiveness of the tumor, various authors and megavoltage radiation may help to reduce the rate of have documented an increased rate of recurrence in Grade malignant transformation that was seen during the earlier III lesions. 15,18 This could be due to the difficulty in achieving era of orthovoltage radiation. 39 complete clearance once the tumor has breached its normal anatomic boundaries and extended into soft tissue.

EMBOLIZATION
The principles of management remain the same even in Unresectable GCTs (e.g., certain sacral and pelvic tumors) recurrent tumors. Steyern et al. retrospectively studied can be managed with transcatheter embolization of (n=137) local recurrence of GCT in long bones following their blood supply. Since flow reconstitution invariably treatment with curettage and cementing. They concluded occurs, embolization is performed at monthly intervals that local recurrence after curettage and cementing in long until significant pain palliation is achieved. Subsequent bones can generally be successfully treated with further embolizations are performed when there is symptomatic curettage and cementing, with only a minor risk `of or radiographic relapse of the tumor. 3,44 Tumors in areas increased morbidity. 37 This suggests that more extensive amenable to surgical resection also benefit by preoperative surgery for the primary tumor in an attempt to obtain embolization in an attempt to reduce the amount of wide margins is not the method of choice, since it leaves intraoperative blood loss. the patient with higher morbidity with no significant gain with respect to cure of the disease. A recent study has shown that rinsing of morcellized bone grafts with bisphosphonates prevents resorption and is likely to reduce the risk of mechanical failure. Though this was studied during revision total hip replacement using morcellized compacted bone allograft, the same principle may possibly be applicable to bone grafts used to fill defects after curettage. 47 .

METASTASIS IN GCTS
The incidence of metastases is estimated to be from 1-6%. The metastatic lesions are histologically identical to the primary lesions, showing no tendency to dedifferentiate. The majority of metastatic lesions are to the lung. Solitary metastasis to regional lymph nodes, the mediastinum and the pelvis have been reported, as has involvement of the scalp, bone and paraaortic nodes. [48][49][50][51][52] The mean interval between the onset of the tumor and the detection of lung metastases

MALIGNANT GCT
There are mainly two kinds of malignant GCT. The primary a high-grade osteosarcoma, MFH or fibrosarcoma. These have a poor prognosis, particularly the radiation-induced sarcomas.
GCT though benign is locally aggressive and the surgeon needs to strike a balance during treatment between reducing the incidence of local recurrence while preserving maximal function [ Figure 6]. In 1912 Joseph Bloodgood was the first to refer to this lesion as "giant cell tumor". His suggestions that this tumor was preferably treated by curettage with chemical cauterization and bone grafting are still widely followed. 54 Current literature too suggests that intralesional curettage strikes the best balance between controlling disease and preserving optimum function in the majority of the cases though there may be occasions where extent of the disease mandates resection to ensure adequate disease clearance.
Between 10-20% of tumors would still recur in spite of our  IJO -April -June 2007 / Volume 41 / Issue 2 best efforts. The principles governing the management of recurrent tumors remain the same as it is believed that more extensive surgery in an attempt to obtain wider margins leaves the patient with higher morbidity with no significant gain with respect to cure of the disease.