Giant cell tumor of bone

INTRODUCTION — Giant cell tumor of bone (GCTB) is a relatively rare, benign, but locally aggressive osteolytic skeletal neoplasm of young adults. First recognized in 1818 [1], it was not until 1940 that GCTB was formally distinguished from other nonmalignant tumors of bone, such as aneurysmal bone cyst, chondroblastoma, and nonossifying fibroma [2]. (See "Nonmalignant bone lesions in children and adolescents".)

Although regarded as a benign tumor, GCTB represents a continuum of neoplasms and clinical behavior that is not predictable based on clinical, radiographic, or histologic features. GCTB can be locally aggressive, and it has a propensity to recur locally after curettage alone. Furthermore, in approximately 2 to 3 percent of cases, distant metastases occur, most often to the lungs. However, pulmonary metastases do not carry the same connotation as metastases associated with malignant tumors, such as lung cancer or sarcoma. In most cases, clinical behavior is benign, and metastatic disease does not lead to the death of the patient, hence the designation "benign pulmonary implants." Rarely, GCTB undergoes true malignant transformation.

This topic review will discuss the epidemiology, clinical and imaging features, staging, pathology and molecular pathogenesis, and treatment approaches for GCTB. The epidemiology, clinical presentation, and diagnosis of bone metastases due to other primary tumors in adults are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

EPIDEMIOLOGY — In the United States, GCTB accounts for approximately 3 to 5 percent of all primary bone tumors and 15 to 20 percent of all benign bone tumors [3,4]. A slightly higher incidence was suggested in a population-based series from the Swedish Cancer Registry; of the 4625 bone tumors diagnosed over a 53-year period, 505 (11 percent) were GCTB [5]. Asian populations have a significantly higher incidence than Western populations. In China, GCTB represents approximately 20 percent of all primary bone tumors [6,7].

However, in general, these tumors are rare. A population-based registry series from Sweden suggests an incidence rate of 1.3 per million persons per year [8].

GCTB usually occurs after skeletal maturity, with a peak incidence in patients' 20s and 30s, and there is a slight female predominance [3,9-11]. The disease is rare before the age of 20. Patients who develop GCTB before epiphyseal closure tend to have a higher incidence of vertebral primary tumors and multicentricity as compared with those who develop the lesion after skeletal maturity [12,13]. However, this has not been seen in all series [14].

A related condition, central giant cell granuloma is a destructive bone lesion of the small bones of the hands and feet, facial bones, skull, and jaw containing multinucleated giant cells; it is a nonneoplastic, reactive condition predominantly seen in children and adolescents [15,16].

Risk factors are generally unknown. However, there is an increased incidence of GCTB in patients with Paget disease of bone. They typically occur in the skull or pelvic bones of patients who have longstanding polyostotic disease, and they also can arise in nonosseous tissues (extraskeletal osteoclastoma). There are reports of familial clustering of both Paget disease and GCTB [17,18]. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

Interestingly, the rare congenital sporadic Noonan syndrome is associated with predisposition to giant cell tumors, especially of the jaw [19-22]. (See "Causes of short stature", section on 'Noonan syndrome'.)

HISTOGENESIS AND MOLECULAR PATHOGENESIS

Histogenesis — The histogenesis, or specific cellular origin, of GCTB remains uncertain. It is also unclear whether GCTB represents a true neoplasm or a reactive condition [23].

The two dominant cell types within GCTB are giant cells and stromal cells:

●Stromal cells – Some studies suggest that the neoplastic component may be derived from the stromal compartment. However, the stromal cells show no cytologic features of malignancy and are unable to form clones in a semisolid medium [24,25]. It is postulated that the stromal cells are activated not because of some inherent genetic change but instead from local hemorrhage-induced release of red cells and plasma proteins into the matrix.

Neoplastic stromal cell possesses an immature osteoblast phenotype, part of whose transcriptional repertoire includes markers of early osteoblast lineage, including receptor activator of nuclear factor kappa B (NF-kB) ligand (RANKL) [26]. It is also possible that unidentified reciprocal signals from the giant cells may be involved in maintaining the immature state of the stromal cells. (See 'Molecular pathogenesis' below.)

Sclerostin expression on the stromal cells, but not on the giant cells, has also been associated with aggressive and symptomatic presentations of GCTB [27].

●Giant cells – Most studies demonstrate a lack of clonal cytogenetic structural aberrations within the giant cells found within GCTB [28-30]. However, the following molecular features are generally considered "proof" of the neoplastic nature of GCTB:

•At least one array-based comparative genomic hybridization study has identified 20q11 amplifications in 54 percent of GCTB [31].

•Centrosome amplification has been described in GCTB and appears to be correlated with recurrence [32]. Furthermore, increased telomerase activity and prevention of shortening of the telomeres have been commonly reported in GCTB [33].

•Data suggest overexpression of p53 in 20 percent of GCTB, consistent with mutation of the gene, which is associated with an increased risk of recurrence and metastasis [34].

•Pathogenic variants in the H3 histone family 3A (H3F3A) gene are also present in over 90 percent of GCTB. These molecular alterations may lead to epigenetic histone modifications and drive tumorigenesis. They are restricted to the stromal cell population and are not detected in osteoclasts or their precursors [35]. Although this is the only recurring pathogenic variant that has been described, its presence does not seem to adequately explain the histogenesis of GCTB [36].

Molecular pathogenesis — RANKL appears to be critical to the pathogenesis of GCTB. Under normal physiologic conditions, osteoclast formation requires an interaction with cells of osteoblastic lineage, which may depend on cell-cell contact, and the interaction of RANKL (a member of the tumor necrosis factor [TNF] ligand family, also known as osteoclast differentiation factor [ODF] or TNF-related activation-induced cytokine [TRANCE, MIM 60264]) with its receptor (RANK) (figure 1) [37-39]. RANK is highly expressed on monocytes, while RANKL is expressed by a variety of cell types, including stromal cells and lymphocytes. A variety of coregulatory molecules also participate in osteoclast formation, including colony-stimulating factor 1 (CSF1), vitamin D, parathyroid hormone (PTH) and PTH-related protein, and prostaglandins. The subject of skeletal development is discussed in detail separately. (See "Normal skeletal development and regulation of bone formation and resorption".)

RANKL is highly expressed by the stromal cells within GCTB [26,29,40,41]. The stromal cells secrete factors that can prevent or regulate osteoclastogenesis; this includes osteoprotegerin, which blocks osteoblast/osteoclast interaction and functions as a secreted natural negative regulator of RANKL [38,42]. Central giant cell granuloma, a related condition, contains abundant multinucleated cells that also express high levels of RANKL [43]. (See 'Epidemiology' above.)

It is thought that RANKL expression by the osteoblast-like mononuclear stromal cells stimulates recruitment of osteoclastic cells from normal monocytic preosteoclast cells. The osteoclastic giant cells then actively absorb host bone via a cathepsin K and matrix metalloproteinase 13 (MMP-13)-mediated process, which would account for the osteolysis associated with these tumors [42,44,45].

However, the underlying basis for the high levels of expression of RANKL by the stromal cells has not been clarified, since it does not appear that there is amplification or translocation of the RANKL gene (which is at the chromosome 13q14 locus). Some data suggest that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) is overexpressed and regulates RANKL, but it is unclear what drives C/EBPbeta expression [46]. Noonan syndrome, variants of which are associated with giant-cell-rich lesions, is reportedly linked to germline mutations in the tyrosine protein phosphatase nonreceptor type 11 (PTPN11) or the son of sevenless homolog 1 (SOS1) genes [21,47-49]. A link to RANKL expression has not been reported.

The most compelling data supporting the importance of RANKL signaling in the pathogenesis of GCTB come from various clinical trials of denosumab, which provided proof of concept that inhibiting RANKL signaling is a powerful and effective strategy in this disease. While there is much that remains to be learned about the molecular pathogenesis of GCTB, studies have led to the identification of RANKL as a major molecular target for therapy. (See 'Neoadjuvant denosumab' below and 'Denosumab for persistently unresectable or metastatic disease' below.)

CLINICAL PRESENTATION AND IMAGING — The most common presentation of GCTB is pain, swelling, and limitation of joint movement at the primary site. The most commonly affected sites are the meta-epiphyses of the long bones, usually around the knee (figure 2); approximately one-half of all cases affect the distal femur or proximal tibia. Other relatively common long bone locations include the distal radius, proximal femur, and proximal humerus. Although often characterized as an epiphyseal tumor and included in the differential diagnosis of epiphyseal tumors such as chondroblastoma, the radiographic epicenter of typical giant cell tumors is in the metaphysis, with extension of the tumor down to the subchondral bone. Less commonly involved sites include the vertebral bodies, pelvis, sacrum, skull and craniofacial bones, and small bones of the hands and feet. Patients with tumors in the axial skeleton may present with neurologic signs and symptoms.

In approximately 10 to 35 percent of patients, thinning of the bone cortex in weight-bearing regions can result in a pathologic fracture [50-53]. The articular surface may be involved. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma", section on 'Clinical presentation'.)

Most cases are solitary; multicentric GCTB accounts for less than 1 percent of the total reported cases [12]. As noted above, patients with multicentric disease tend to be younger than those with a solitary GCTB. (See 'Epidemiology' above.)

In rare circumstances, patients may present with metastatic disease, mostly in the lung [54]. However, in general, lung metastases more typically arise in the setting of locally recurrent disease. (See 'Natural history' below.)

Imaging workup — Imaging of the primary site is indicated in all patients and includes plain radiographs and cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI], with and without contrast). Chest CT is recommended in guidelines from the National Comprehensive Cancer Network (NCCN) [55] to evaluate for lung metastases. However, given that metastatic spread is most common following initial surgical intervention [10], it is reasonable to obtain only a plain chest radiograph at the time of diagnosis and reserve chest CT for patients who have locally recurrent disease. Radionuclide bone scan may be helpful in staging multicentric disease, but there is no clear consensus on the indications for obtaining a bone scan.

Modern imaging techniques to determine the extent of disease involvement incorporate a combination of anatomic (radiograph, CT, MRI) and functional (bone scan, positron emission tomography [PET]) scans. On plain radiographs, GCTB typically appears as an expansile, eccentrically placed lytic area, which is the result of intratumoral hemorrhage. The lesion normally involves the epiphysis and the adjacent metaphysis (figure 3), and there is frequent extension to the subchondral plate, sometimes with joint involvement. Matrix calcification and reactive periosteal new bone formation are typically absent [56].

Compared with plain radiographs, CT scans provide a more accurate assessment of cortical thinning and penetration, and the presence or absence of bone mineralization. Mineralization within the tumor suggests the presence of a primary osteosarcoma, which needs to be ruled out. (See "Bone tumors: Diagnosis and biopsy techniques".)

MRI is particularly useful for assessing involvement of the surrounding soft tissue, including neurovascular structures, and the extent of subchondral extension into the adjacent joints. The characteristic findings on MRI are an expansile hypervascular mass with cystic changes, heterogeneous low to intermediate signal intensity on T1-weighted images, and intermediate to high intensity on T2-weighted images [57,58]. Large amounts of hemosiderin are often present, accounting for areas of low signal intensity on both T1-weighted and T2-weighted images [56].

Based on the radiographic findings, the differential diagnosis may include a lytic metastasis (particularly an expansile, highly vascular metastasis from renal cell or thyroid carcinoma), a primary malignant bone tumor (such as a telangiectatic osteosarcoma or clear cell chondrosarcoma), a brown tumor of hyperparathyroidism, an aneurysmal bone cyst, or nonossifying fibroma. (See "Nonmalignant bone lesions in children and adolescents".)

Chest CT may be indicated at initial diagnosis to evaluate for the presence of pulmonary metastases. However, given that metastatic spread is most common in the setting of local recurrence, chest CT imaging is generally reserved for patients who have locally recurrent disease. For patients with fully treated disease and no evidence of disease recurrence, the approach to chest imaging for posttreatment surveillance is discussed below. (See 'Posttreatment surveillance' below.)

Radionuclide bone scan may be helpful in staging multicentric disease, but there is no clear consensus on the indications for obtaining a bone scan. Changes on bone scan, typically decreased uptake of radiotracer in the center of the tumor, are not specific for GCTB. Aneurysmal bone cysts have a similar appearance.

There are limited data regarding the utility of fluorodeoxyglucose (FDG)-PET for newly diagnosed GCTB. Unlike many benign bone tumors, GCTB accumulates the FDG tracer, presumably because the osteoclast-like giant cells are intensely metabolically active [59,60]. However, whether there are any advantages to evaluation with FDG-PET as compared with conventional imaging with CT, MRI, and bone scan is unclear.

On the other hand, changes in FDG uptake over time correlate with tumor metabolism and angiogenic activity [61]. In our experience, FDG-PET is a highly sensitive biomarker of response to targeted therapeutics, which may be useful in clinical situations where early confirmation of response is clinically indicated. (See 'Denosumab for persistently unresectable or metastatic disease' below.)

CLASSIFICATION AND STAGING — Different classifications of GCTB based on histology [2] and clinical/radiographic appearance [50,51,62-64] have been proposed. As an example, the Campanacci grading system stratifies patients according to clinical and radiographic appearance as follows [50]:

●Grade I – Intraosseous lesions with well-marginated borders and an intact cortex.

●Grade II – More extensive intraosseous lesions having a thin cortex without loss of cortical continuity.

•IIA – Without pathologic fracture.

•IIB – With pathologic fracture.

●Grade III – Extraosseous lesions that break through the cortex and extend into soft tissue.

Classification systems such as these may influence the type or extent of surgery. However, such classification systems are of limited pathologic and prognostic utility. They do not correlate well with histologic appearance and provide little prognostic information regarding the risk of local recurrence or metastatic behavior.

Some use the Enneking classification for benign tumors of the musculoskeletal system for GCTB (table 1) [63,65], and a complementary system for tumors located in the vertebrae has been proposed (figure 4) [62,64] and used by some clinicians [11,65,66]. However, use of these staging systems is not universally accepted.

The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) for sarcoma does not apply to GCTB.

NATURAL HISTORY — Despite the generally benign nature of most GCTB, the spectrum of disease behavior is highly variable and unpredictable. There are varying degrees of local aggressiveness, and focal symptoms typically result from bony destruction, cortical breakthrough, and expansion into soft tissues. Disease within the axial skeleton, which is often unresectable, can cause severe and debilitating local complications.

Some cases behave in a malignant fashion. However, the term "malignant" GCTB includes multiple entities and therefore can be confusing.

Pulmonary metastases — In approximately 2 to 3 percent of cases of extremity giant cell tumors, metastases develop, most frequently to the lungs. The rate may be higher for spine GCTB, possibly because of the higher rates of subtotal resection and local recurrence in this subset [67].

In general, pulmonary metastases from GCTB do not carry the same connotation as metastases from other solid tumors, such as sarcoma. For most patients, the clinical outcomes remain consistent with the generally benign character of the tumor [68], hence their designation as "benign" pulmonary implants [10,54,56,67,68]. However, in a small number of cases, pulmonary metastases (particularly if accompanied by metastases in other sites [69]) contribute to death [13,28].

In most series, the large majority of cases of lung metastases follow a local recurrence [70,71]. As an example, in one report of 333 patients who underwent surgery for GCTB and were followed for at least two years, 25 developed lung metastases, 80 percent of which were preceded by a local recurrence [70]. Of the 118 patients with a local recurrence, 20 developed metastases (17 percent); in contrast, only 2 percent of the 215 patients without a local recurrence developed lung metastases.

However, this is not a universal finding. In another series of 470 patients with GCTB diagnosed over a 20-year period at Tata Memorial Hospital in India, 24 developed distant metastases, 21 involving the lungs [10]. Only 13 patients (54 percent) had a local recurrence before or at the time of metastatic spread. Other involved sites were the scalp, calf muscle, and regional lymph nodes.

Other risk factors for pulmonary metastases from GCTB are young age (mean 25 versus 34 years of age) at time of diagnosis, Enneking stage III disease (table 1), and axial as opposed to appendicular location [72]. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Tumor staging'.)

Malignant transformation

True spontaneous malignant transformation of GCTB has been reported [73-80]. The term "malignancy in giant cell tumor" is used by the World Health Organization (WHO) to designate high-grade sarcoma arising in GCTB (primary) or at the site of previously documented GCTB (secondary) [56].

The incidence of spontaneous malignant transformation of GCTB is not known since most reports are single cases. However, population-based registry data suggest that malignant GCTB comprises up to 8 percent of all diagnoses of GCTB [8]. It is not clear to what extent these cases represent true transformation of benign GCTB. Benign GCTB has molecular alterations that are limited to H3.3A or H3.3B, whereas malignant GCTB typically has features consistent with osteosarcoma, including additional driver mutations, high mutational burden, and aneuploidy. However, the mechanism of transformation from benign to malignant GCTB is unknown [81]. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Molecular genetics'.)

Radiation therapy (RT) is reported to increase the risk of malignant transformation. However, some cases of "malignant transformation" in GCTB following RT represent radiation-associated sarcoma [82,83]. In other cases, when primary malignant GCTB is discovered, it may represent a primary bone sarcoma with prominent areas of hemorrhage and giant cell reaction that was missed at initial diagnosis, rather than malignant transformation of GCTB [84]. (See "Radiation-associated sarcomas".)

The incidence of malignant transformation associated with denosumab therapy is rare (less than 1 percent) and typically occurs within the first year of treatment; in contrast, malignant transformation associated with RT often takes longer to develop [85]. (See 'Denosumab for persistently unresectable or metastatic disease' below.)

The prognosis for true malignant transformation of GCTB is worse than benign GCTB and comparable to other high-grade sarcomas. In observational studies, five-year overall survival ranges between 50 and 82 percent [73,76,78].

DIAGNOSIS — A biopsy is required to establish the diagnosis. Grossly, GCTB is a fleshy, reddish tumor, often containing cystic and hemorrhagic areas. The tumor may breach the cortex and extend into soft tissues, and there is little or no periosteal reaction. (See "Bone tumors: Diagnosis and biopsy techniques".)

Histology — Microscopically, the tumor is composed of sheets of round to oval, polygonal or elongated mononuclear cells that are interspersed with uniformly distributed, large osteoclast giant cells [56]. When the tumor is present in the lungs, the histologic features are identical to the primary tumor, including the presence of giant cells.

The prominent multinucleated cells, which may exceed 50 percent of the total cell content of the tumor, are thought to derive from circulating monocytes that have converted into osteoclasts in the osseous environment. This conclusion is supported by light, ultrastructural, and immunologic marker studies [29,42,86-88].

It is generally accepted that the characteristic large osteoclastic giant cells are not neoplastic. The mononuclear cells, which represent the neoplastic component, are thought to arise from primitive mesenchymal stromal cells [24]. These cells have characteristics of osteoblast progenitors [26,89] and express receptor activator of nuclear factor kappa B (NF-kB) ligand (RANKL), a growth factor that is essential for the recruitment of osteoclasts by osteoblasts and their maturation under normal physiologic conditions. (See 'Histogenesis and molecular pathogenesis' above.)

Testing for the presence of mutations in the H3 histone family 3A (H3F3A) gene may help to support the diagnosis when it is in doubt. (See 'Differential diagnosis' below and 'Molecular pathogenesis' above.)

The distinction between benign and "malignant" giant cell tumors may be difficult since the transformed element (atypical cells) may be relatively difficult to detect in a "sea" of reactive giant cells. This problem is exacerbated by the sampling limitations inherent in the use of core or fine needle biopsies.

Importantly, histologic grading does not appear to be of value in predicting either locally aggressive behavior or the development of metastases [56]. The stromal cells show no cytologic features suggestive of malignancy unless associated with malignant transformation (which is rare). (See 'Natural history' above.)

Differential diagnosis — The histologic differential diagnosis of GCTB includes other giant-cell-rich and osteoclast-rich tumors, including aneurysmal bone cysts, nonossifying fibroma, fibrous metaphyseal defects, giant-cell-rich osteosarcoma, chondroblastoma, brown tumors associated with hyperparathyroidism, and metastatic cancer [9]. (See "Nonmalignant bone lesions in children and adolescents".)

As noted above, mutations in the H3F3A gene can serve to distinguish GCTB from other entities because they are identified in up to 96 percent of cases arising in the long bones [90,91]. Immunohistochemical staining using a monoclonal antibody directed against the G34W mutated site of H3F3A is positive in 95 to 100 percent of GCTB arising in the long bones [92]. Notably, in sites rarely involved by GCTB (ie, the small bones of the hands and feet, vertebrae), the G34W mutation and immunohistochemical expression of H3F3A are less frequent (56 and 0 to 42 percent, respectively) [90,93].

However, the presence of a mutation in H3F3A does not entirely exclude malignancy or other osteoclast-rich tumors, such as chondroblastoma, aneurysmal bone cysts, or nonossifying fibroma [35,90]. In particular, chondroblastoma has a high frequency of mutations in histone 3.3 genes [35].

MANAGEMENT OF LOCALIZED APPENDICULAR TUMORS — Surgery is the treatment of choice for GCTB involving the long bones. Disease involving the pelvis and spine is more difficult to control surgically. Such patients should be referred for a multidisciplinary evaluation that incorporates the input of a surgical (orthopedic) oncologist, medical oncologist, and radiation oncologist with experience in the treatment of GCTB. (See 'Management of localized axial tumors' below.)

Surgical candidates at presentation

Choice of surgical intervention — Surgical options for treatment of appendicular GCTB range in extent and invasiveness from intralesional options to en bloc resection with or without reconstruction.

The type of surgery chosen depends on many clinical factors, such as site, size, extent of the tumor in relation to the surrounding structures (ie, intraosseous versus extraosseous), and presence of pathologic fracture. The choice of surgical intervention must balance the risk of recurrence with the morbidity of the surgical intervention and the postoperative functional outcomes. Observational data report higher rates of local recurrence with intralesional curettage relative to more extensive surgery, including studies with long-term follow-up [50,52,94,95]. Even with the addition of an adjuvant during "extended" curettage, the risk of recurrence is higher than that with aggressive resection techniques in most studies [52,94,96]. For example, in a large retrospective study with a decade of follow-up of 384 patients with primary or recurrent GCTB, recurrence rates were higher in those treated with intralesional curettage (either with or without an adjuvant) versus those treated with wide excision (33 versus 2 percent) [94]. Among those treated with intralesional curettage, the addition of bone cement as an adjuvant decreased the local recurrence rate to 22 percent.

Regardless of the choice of surgical intervention, it is generally accepted that the status of the surgical resection margins remains the best predictor of recurrence rates [50,95].

Our general approach is as follows:

●For most primary or recurrent intraosseous lesions (ie, Campanacci grade I or II lesions (see 'Classification and staging' above)), we suggest "extended" intralesional curettage, in which the surgical margins obtained through simple curettage are extended using an adjuvant to treat microscopic locoregional disease several millimeters beyond the limits of mechanical curettage [97]. Extended intralesional curettage may result in a large bone defect, depending on the size of the tumor, and may be followed by internal fixation. Simple curettage results in high local recurrence rates, so this approach alone is generally inadequate to obtain locoregional disease control. Further details on the approach to extended intralesional curettage and available adjuvants are discussed below. (See 'Intraosseous disease' below.)

Exceptions are made for select cases of pathologic fracture, as well as for tumor involvement of expendable bones, such as the proximal fibula or distal ulna (which are typically treated with en bloc resection, as discussed below). An additional possible exception is made for intraosseous involvement of the distal radius and proximal femur. Although en bloc resection is typically preferred, extended intralesional curettage may be an appropriate alternative for those with intraosseous involvement of these disease sites, and such patients may be evaluated for both procedures.

En bloc resection, with or without reconstructive surgery, is typically offered to the following subsets:

●Extraosseous extension – We typically suggest en bloc resection for those with extensive extraosseous extension (eg, Campanacci grade III (see 'Classification and staging' above) or Enneking stage III disease (table 1)), especially those with involvement of the distal radius or proximal femur. In these two anatomic regions, the bony confines are more limited, resulting in more frequent extraosseous extension. Intralesional curettage is less preferred in these areas due to the small size of the bones relative to those in more frequent sites of disease (eg, distal femur and proximal tibia). Additionally, the small volume of these bones limits the exothermic effects of bone cement and may potentially result in higher rates of recurrence.

Additionally, for patients with proximal femur involvement, we prefer en bloc resection because of the high risk of fracture after intralesional curettage, the risks of avascular necrosis, and the availability of good arthroplasty reconstruction techniques for the surgical deficits. Intralesional curettage, while less preferred, is an option for proximal femoral disease without articular cartilage damage, displaced fracture, or substantial soft tissue extension [98]. (See 'Extraosseous disease' below.)

However, select patients may be treated with intralesional curettage with adjuvant therapy, similar to those with intraosseous lesions, rather than more extensive surgery, if such an approach is likely to improve postoperative functional outcomes and patients are informed of the potentially higher recurrence risk. As an example, for those with extraosseous involvement of large bones (eg, distal femur and proximal tibia), extended intralesional curettage is generally preferred.

●Select cases of pathologic fracture (eg, gross damage to the articular surface and dislocated intra-articular fracture) – En bloc resection is generally recommended if the articular surface is grossly damaged or if there is a dislocated intra-articular fracture that cannot be stabilized with a combination of bone cement and internal fixation techniques [52]. In some series, pathologic fracture has been a risk factor for local recurrence [52,99], leading some to suggest that intralesional curettage should be avoided in such cases. However, our approach to the management of patients with GCTB and pathologic fracture is individualized depending on the nature of the fracture and the implications for reconstructive outcomes [100,101].

Pathologic fracture, in and of itself, is not a contraindication to curettage. For example, one meta-analysis of over 3200 patients with GCTB (58 percent with pathologic fracture at diagnosis) treated with either resection or curettage demonstrated no difference in the local recurrence rates between the two treatment options [53]. Similarly, another study with more contemporary surgical techniques suggested that the locoregional recurrence risk may be similar with curettage plus adjuvant therapy versus surgery for those with pathologic fractures, with better functional outcomes associated with curettage [102]. Among 46 patients with GCTB, curettage with adjuvant therapy yielded similar recurrence rates (1 of 13 patients [6 percent]) relative to wide excision (2 of 33 patients [6 percent]) and a better Musculoskeletal Tumor Society (MSTS) functional score [102,103]. However, time to recurrence was shorter in those treated with curettage (six months) versus those treated with wide excision (11 and 82 months).

●Tumor involvement of expendable bones (eg, proximal fibula or distal ulna) – Lesions involving the proximal fibula or distal ulna are considered to involve "expendable bones" and are traditionally treated with en bloc resection because they typically require limited soft tissue reconstruction. For example, those with resection of the proximal fibula typically only require reconstruction of the lateral collateral ligament. Less invasive surgical options other than en bloc resection may also be offered to those with disease involving other locations where more invasive surgical approaches would result in major articular reconstruction with loss of function.

Intraosseous disease — For most primary or recurrent intraosseous lesions (ie, Campanacci grade I or II lesions), we recommend intralesional curettage with adjuvant therapy (ie, extended intralesional curettage), rather than more extensive surgical resection. Exceptions are made for select cases of pathologic fracture, as well as for expendable bones, such as the distal ulna and proximal fibula (which are typically treated with en bloc resection). (See 'Choice of surgical intervention' above.)

When curettage is used, we also recommend the addition of adjuvant therapy with bone cement (polymethylmethacrylate [PMMA]), rather than simple curettage alone, in order to reduce the risk of local recurrence. Adjuvants are mechanical, thermal, or chemical therapies that treat microscopic locoregional disease extending several millimeters beyond the limits of mechanical curettage [104]. Since the standard margin achievable with simple curettage is unacceptable, the margin is "extended," usually through a combination of mechanical (eg, burring) and additional thermal or chemical means (eg, phenol, cryotherapy, argon beam coagulation, or plasma beam). The goal of the extended margin is to treat microscopic locoregional disease several millimeters beyond the limits of mechanical curettage [97]. There are limited data on the use of denosumab as an adjuvant after intralesional curettage, and this approach may be associated with a higher risk of local recurrence. (See 'Is there a role for postoperative denosumab?' below.)

In order to accomplish an extended intralesional curettage, the lesion must first be completely exteriorized with a large access cortical window in order to assure that the surgeon is not overlooking disease hidden behind an overhanging edge of bone. Treatment in this fashion leaves a large bone defect, depending on the size of the tumor. The large created defect is then filled with an adjuvant, such as PMMA bone cement or bone graft material. Of note, this defect potentially increases the risk of postoperative fracture (2 to 14 percent). However, this fracture risk may be reduced by bone grafting of the subchondral bone and/or prophylactic stabilization [105,106].

In patients treated with intralesional curettage, the addition of an adjuvant decreases local recurrence rates relative to curettage alone, although data are occasionally conflicting. In most observational series of patients treated with intralesional curettage with a local adjuvant, local recurrence rates ranged between 6 and 22 percent [52,94,102,107,108]. For example, in a retrospective study from the Scandinavian Sarcoma Group (SSG) of 194 patients undergoing intralesional surgery, recurrence rates were lower with bone cement as an adjuvant versus no cement (22 versus 56 percent) [52]. Recurrence rates in another retrospective study of over 300 patients were similar [94].

In contrast, one large series suggested no benefit from the addition of a local adjuvant to curettage, provided there is adequate surgical tumor removal [109]. In a large meta-analysis of studies including approximately 400 patients, recurrence rates were similar among those treated with curettage plus an adjuvant versus curettage alone (20 versus 23 percent) [109]. The lack of benefit from the addition of an adjuvant to curettage was attributed to meticulous surgical removal of the tumor.

Various adjuvants evaluated in an attempt to decrease local recurrence rates after intralesional curettage include bone cement (PMMA) [52,94,110], bone grafts [52], aqueous zinc chloride [111], phenol [112,113], cryotherapy with or without cement [107,114,115], argon beam coagulation [74], local and intravenous zoledronic acid [116], and a high-speed burr to remove peritumoral bone [13,117]. Certain adjuvants (eg, bone cement and grafts) also act as filling agents to stabilize the surgical cavity after curettage.

While there are no randomized trials comparing different adjuvants, bone cement has emerged as the preferred option because observational data suggest that this approach decreases the risk of local recurrence relative to curettage alone [52,94,107] or curettage with bone graft as an adjuvant [52,108]. In addition, filling the cavity with bone cement allows immediate weight bearing postoperatively, and the heat (ie, exothermic effect) induced during the setting and curing of the cement is thought to kill any remaining tumor cells [118,119]. Furthermore, the radiodense appearance of a cement-filled cavity is ideal to permit early identification of local recurrences on radiograph and computed tomography (CT), which typically present on such imaging as an enlarging radiolucency. Such recurrences may be more difficult to detect when a bone graft or another adjuvant has been used, as these undergo varying stages of radiolucency and sclerosis over the process of incorporation into the bone.

Secondary degenerative joint disease (DJD) is one long-term adverse outcome associated with bone cement. Secondary DJD occurs because the cement impacts the adjacent cartilage overlying the subchondral bone. While the DJD can progress on pre- and postoperative plain films, it is not typically severe enough to require a total knee replacement. [120,121]

Extraosseous disease — Lesions with extraosseous extension (ie, Campanacci grade III lesions (see 'Classification and staging' above) or Enneking stage III lesions (table 1)) are typically treated with en bloc resection [122-124], although some exceptions may exist. (See 'Choice of surgical intervention' above.)

In one retrospective series, recurrence rates were low with curettage alone in patients whose tumors were confined to bone, but they were higher in those with extraosseous disease (7 versus 29 percent) [125]. In some studies, recurrence rates in patients with extraosseous disease treated with intralesional curettage alone were as high as 36 percent, and they may be higher at certain sites, such as the distal radius and proximal femur [50,94,96,102,108,126].

However, given the benign nature of giant cell tumors, select patients may be treated with intralesional curettage with an adjuvant, rather than more extensive surgery, if such an approach is likely to improve postoperative functional outcomes and patients are informed of the potentially higher recurrence risk [95,100-102,108,127]. However, this is not a widespread approach. If curettage is used, it should be followed by an adjuvant, using an approach analogous to intraosseous disease. (See 'Choice of surgical intervention' above and 'Intraosseous disease' above.)

Reconstruction techniques — There is clinical variability in reconstruction techniques after en bloc resection, with most studies in patients with distal radial GCTB [128-131]. Selecting a reconstruction technique is typically based upon the ability to preserve limb/joint function, risk of surgical morbidity, patient satisfaction outcomes, and the surgeon's expertise and preference.

In one systematic review of reconstructive options for GCTB of the distal radius treated with wide resection, arthroplasty, which preserves joint function, was the most commonly used technique [128]. Arthroplasty with a non-vascularized fibula provided the best outcomes, including lower morbidity. Other reconstruction techniques with good satisfaction rates included arthroplasty with allograft and custom-made prostheses. Arthrodesis was mainly reserved for patients who performed heavy manual labor or those who failed arthroplasty. Further details on these reconstruction techniques, which are similar to those used in bone sarcomas, are discussed separately. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Reconstruction techniques'.)

Is there a role for postoperative denosumab? — Data are limited on the use of denosumab as an adjuvant after curettage and following resection of GCTB [132,133], and it is not our routine practice to administer it in this setting. The effect of adjuvant denosumab on local recurrences is debatable, and this approach remains investigational pending further confirmatory studies.

In one retrospective observational study, the addition of denosumab following curettage was associated with an increased risk of local recurrence [132]. The mechanism of recurrent disease is attributed to preservation of both tumor cells and normal bone by denosumab; the tumor cells subsequently reactivate when treatment is discontinued.

The use of denosumab in the neoadjuvant and metastatic settings is discussed separately. (See 'Neoadjuvant denosumab' below and 'Denosumab for persistently unresectable or metastatic disease' below.)

Nonsurgical candidates at presentation — For patients with potentially resectable GCTB but where initial surgery would be associated with functional compromise or significant morbidity, initial neoadjuvant therapy with denosumab followed by resection may be offered rather than initial resection. (See 'Neoadjuvant denosumab' below.)

For patients in whom surgery is contraindicated due to the risk of severe morbidity, options include radiation therapy (RT), arterial embolization, and systemic therapy including denosumab. (See 'Nonsurgical candidates' below.)

The antitumor benefits of long-term use of denosumab in either clinical setting (ie, neoadjuvant or unresectable disease) must be balanced against the potential side effects, including osteonecrosis of the jaw. (See "Medication-related osteonecrosis of the jaw in patients with cancer".)

Neoadjuvant denosumab — For patients with potentially resectable GCTB for whom initial surgery would result in unacceptable functional compromise or significant morbidity (ie, loss of limb or joint removal), we offer treatment with denosumab rather than initial resection. Denosumab is approved by the US Food and Drug Administration (FDA) for this indication [134]. We typically administer denosumab at 120 mg subcutaneously every 28 days, with two additional loading doses on days 8 and 15 during the first month of therapy. Although the optimal duration of preoperative denosumab is not established, we limit the pretreatment duration to the minimum needed to convert the patient to operability, especially given the risks of longer term treatment [135]; in order to achieve this goal, most patients are typically treated for approximately six months. The subsequent timing of surgery is usually based on the degree of improvement observed radiologically.

Further details about the mechanism of action of denosumab, as well as its use in the metastatic setting, are discussed separately. (See 'Histogenesis and molecular pathogenesis' above and 'Denosumab for persistently unresectable or metastatic disease' below.)

The approval of denosumab in the neoadjuvant setting was based on several nonrandomized phase II trials and other observational studies that suggested that this approach reduces tumor burden and local recurrence rates and increases rates of surgical downstaging when used prior to wide en bloc resection [136-140]. However, only one study reports long-term toxicity follow-up, and only a limited number of patients have undergone intralesional surgery, such as curettage, following denosumab. Nevertheless, neoadjuvant denosumab is an appropriate option in carefully selected patients who are adequately informed about the potential risks and benefits. Data are as follows:

●In one open-label phase II trial of approximately 532 adult or adolescent patients with GCTB, a planned cohort of 253 patients with surgically salvageable disease was treated with neoadjuvant denosumab, followed by six doses of postoperative denosumab after complete tumor resection [139,140]. Patients received denosumab for a median of 20 months. In this subset, at a median follow-up of approximately 53 months, 63 percent (157 patients) were able to undergo surgery, and approximately 40 percent (106 patients) were downstaged to less extensive surgery, most commonly curettage. The postoperative recurrence rate was 27 percent.

●In another open-label phase II study, 222 patients with primary or recurrent unresectable GCTB were treated with neoadjuvant denosumab for a median of approximately 14 months [141]. At a median postoperative follow-up of 14 months, among the 116 patients (52 percent) who eventually had surgery (predominantly curettage), the local recurrence rate was 15 percent.

Delineating the appropriate surgical margins following the use of neoadjuvant denosumab may be clinically challenging and may affect the surgical approach [133]. The new osseous tumor matrix and thickened cortical bone that develop with denosumab treatment do not allow the surgeon to delineate the true extent of the tumor and might increase the risk of local recurrence after intralesional therapy [142,143]. In one observational study of 38 patients with primary GCTB treated with neoadjuvant denosumab and curettage, the local recurrence rate was 16 percent for all patients and 21 percent for those treated with second curettage. Nevertheless, joint preservation was still possible in most patients (63 percent) [144]. By contrast, en bloc resection after denosumab therapy is not associated with increased risk of local recurrence [143,145].

Although data on the toxicity of denosumab in the neoadjuvant setting are limited, denosumab appears to be well tolerated overall when administered in this setting [135,140]. As an example, the phase II study discussed above included a subset of 253 patients with GCTB treated with neoadjuvant denosumab for a median of 20 months, followed by resection in 155 patients [140]. In the entire study cohort, at a median follow-up of approximately four and a half years, long-term toxicities were rare, including hypophosphatemia (5 percent), osteonecrosis of the jaw (3 percent), hypercalcemia, and atypical femur fractures (1 percent each). Malignant transformation of benign GCTB into sarcoma was noted in four patients (1 percent).

Other long-term toxicities associated with denosumab, including malignant transformation into high-grade sarcoma and osteonecrosis of the jaw, are discussed separately. (See 'Denosumab for persistently unresectable or metastatic disease' below.)

Recurrent disease (localized) — The treatment of localized recurrent disease is determined based on surgical candidacy and is detailed below.

Surgical candidates — Locally recurrent, potentially resectable GCTB can be successfully treated with further curettage and local adjuvant therapy, with only a minor risk of increased morbidity [95,108,146-148]. More extensive surgery is indicated for a second or later recurrence. (See 'Choice of surgical intervention' above.)

Three-fourths of all local recurrences develop within two years, and the remainder typically develop at a median of five years [52,78,99,147,149]. However, given that rare local recurrences and secondary sarcomas may develop many years after initial treatment, we suggest lifelong follow-up, at least annually [65,150-155].

Local recurrences after en bloc resection carry a relatively poor prognosis [156]. In an observational study of 205 patients treated with en bloc resection for GCTB, there were high rates of local re-recurrence (41 percent), distant metastases (35 percent), malignant transformation (7 percent), and death (7 percent).

Given that most cases of pulmonary metastasis develop in patients who have locally recurrent disease, intensified lung surveillance using chest CT or chest radiograph is reasonable in the setting of a local recurrence [13,70,157]. Guidelines from the National Comprehensive Cancer Network (NCCN) [55] recommend this approach for patient surveillance. (See 'Observation versus locoregional therapy for pulmonary metastases' below and 'Posttreatment surveillance' below.)

Nonsurgical candidates — For patients with unresectable, locally recurrent disease, options include RT, arterial embolization, and systemic therapy including denosumab. These patients should also have a screening chest CT to rule out pulmonary metastases, in which case therapy for metastatic disease may be indicated. (See 'Management of unresectable or metastatic disease' below.)

Radiation therapy — GCTB is a radiosensitive tumor, and RT is highly effective, resulting in long-term local control rates ranging from 60 to 84 percent [77,158-164]; rates are lowest for tumors >8.5 cm and for locally recurrent disease [158,162].

RT is a reasonable option if surgery is contraindicated or in a situation where negative surgical margins can only be achieved with unacceptable morbidity. One example of where this might be the case is for a large midline sacral GCTB. Resection of a small sacral tumor to one side of the midline may be possible without unacceptable morbidity if one set of sacral nerves can be preserved, providing reasonable postoperative bladder and bowel function. However, complete resection of a large midline sacral GCTB would necessitate sacrifice of both sets of sacral nerves, leading to permanent double incontinence. (See 'Sacral tumors' below.)

RT has also been used as adjuvant therapy to reduce local recurrence rates after intralesional surgery for spinal GCTB [165,166]. There are no trials comparing RT with a local adjuvant such as bone cement or burring in this setting. (See 'Intraosseous disease' above.)

Given the young age of most of these patients, a major concern with RT is the risk of radiation-associated malignant transformation [160,167,168]. The magnitude of this risk is not definitively known. While several reports cite no increased risk of malignancy in these patients [159,161,169-171], at least one series noted an 11 percent risk of radiation-induced sarcoma among patients undergoing RT for primary or recurrent GCTB [172]. (See "Radiation-associated sarcomas".)

Largely because of concerns about malignant transformation, guidelines from the NCCN [55] suggest that RT be considered only after other options have been exhausted. However, an important point is that the published series included patients treated with older orthovoltage RT techniques, where the dose absorbed by the bone would have been substantially higher than the prescription dose. Lower rates are expected with modern megavoltage irradiation. One series reported a 2 percent rate of malignant transformation in 77 patients treated between 1985 and 2007 with megavoltage RT [77]. Modern techniques, such as intensity-modulated RT, appear promising, but data are preliminary at this stage [173]. In our view, RT using modern techniques remains a reasonable approach for patients with GCTB at a site where surgical margins can only be achieved with unacceptable morbidity (as, for example, with a large midline sacral GCTB with no chance of preserving at least one set of sacral nerve roots) or if the patient is a poor surgical candidate. Regardless, patients must be aware that there is the potential for RT to convert a benign process into a malignant one.

Other therapies — Other therapies for recurrent disease, other than surgery and RT, include locoregional interventions such as arterial embolization and microwave ablation [174,175]. For those who are not candidates for arterial embolization, we offer systemic therapy including denosumab, using a similar approach to that for those with metastatic disease. (See 'Management of unresectable or metastatic disease' below.)

MANAGEMENT OF LOCALIZED AXIAL TUMORS — The treatment of localized axial tumors involving the sacrum and spine is discussed below. The management of localized appendicular tumors is discussed separately. (See 'Management of localized appendicular tumors' above.)

Sacral tumors — Large midline GCTB of the sacrum is difficult to treat and, given limited available evidence, patients should be approached on a case-by-case basis. Surgery carries a high risk of morbidity and disability because there is no chance of preserving at least one set of sacral nerve roots. Furthermore, radiation therapy (RT) carries at least the potential risk of long-term malignant transformation. Successful treatment with arterial embolization has been described, although published experience is limited [176,177]. Systemic therapy with denosumab may be used with surgery (in the neoadjuvant or adjuvant setting [178]) or as an alternative to local therapies when they carry unacceptable morbidity or risk. Treatment must be individualized, balancing the risks of exposure to lifelong denosumab with the risks of RT, both of which are difficult to estimate. (See 'Management of unresectable or metastatic disease' below and 'Radiation therapy' above.)

Spinal tumors — For those with spinal giant cell tumors who are surgical candidates, complete surgical resection should be the goal, particularly if neurologic impairment is evident. For patients with unresectable lesions and with tumors in high-risk locations, we offer denosumab because some patients may have long-term disease control with this approach. Patients should be treated on a case-by-case basis, as each one presents unique challenges.

The treatment of spinal giant cell tumors is challenging. Spinal GCTB have a poorer prognosis overall than do appendicular GCTB, with a higher rate of local recurrence [179]. The best form of local treatment is not established. Intralesional curettage is associated with a high rate of local recurrence, and treatment of a spinal recurrence after intralesional therapy can be demanding and expose the patient to significant surgical risk [11]. Adjuvants such as cement are not generally used in the spinal axis because of the risk of iatrogenic injury to the neural elements due to the exothermic effect.

On the other hand, spinal en bloc resection, while associated with lower rates of local recurrence [11,179,180], is complex and may be impossible due to anatomic constraints. In addition, the level of morbidity or functional loss required to achieve good margins may be significant or unacceptable. However, given the correlation of local recurrence with mortality, en bloc resection should be performed when technically feasible. Increasingly, data suggest success with total en bloc spondylectomy utilizing various approaches at experienced centers for giant cell tumors of the spine [181-183].

Accumulating reports suggest potential benefit for preoperative denosumab, and this approach could be considered for unresectable or high-risk spinal giant cell tumors [145,184-187]. Although there is no consensus on the appropriate indications for initial denosumab, National Comprehensive Cancer Network (NCCN) guidelines support this as an option for locally unresectable GCTB, including that arising in the spine. In some cases, surgery may be avoided. Cases of long-term complete and radiographic regression of both primary and recurrent giant cell tumors of the spine using denosumab have been reported [188,189], although the frequency with which this happens is unclear. (See 'Denosumab for persistently unresectable or metastatic disease' below.)

MANAGEMENT OF UNRESECTABLE OR METASTATIC DISEASE

Choice of therapy — The choice of therapy for those with unresectable or metastatic GCTB is dependent on the extent and location of the disease, the progressive nature of the disease (indolent versus aggressive), symptoms, and patient comorbidities.

We suggest surgical resection for patients with surgically resectable pulmonary metastases who are potentially or actively symptomatic from their disease, due to the potential morbidity of such symptoms. However, other experts may offer observation, given the benign nature of the disease, with surgical intervention as clinically indicated. Radiation therapy (RT) or denosumab may be offered to patients with unresectable pulmonary metastases, those with resectable disease who decline thoracic surgery, or those who relapse after initial thoracic surgery. (See 'Observation versus locoregional therapy for pulmonary metastases' below.)

For patients with more aggressive forms of GCTB who are not candidates for locoregional therapy (eg, surgery or RT), we offer denosumab over other systemic therapies such as bisphosphonates or chemotherapy. (See 'Denosumab for persistently unresectable or metastatic disease' below.)

Observation versus locoregional therapy for pulmonary metastases — The approach to observation versus locoregional therapy is as follows:

●Observation – Local recurrence is accompanied by an increased risk of "benign" pulmonary implants. The clinical outcomes of patients with pulmonary metastases generally remain consistent with the generally benign character of the tumor. Spontaneous regression of pulmonary metastases is also described [68,71,190]. (See 'Natural history' above.)

Given the uncertainty as to the natural history of pulmonary metastases, some centers simply observe these patients [191,192]. If observation is chosen, close monitoring with chest computed tomography (CT) is needed for early detection of tumor progression or other complications.

●Surgery – Surgical resection is often recommended for patients who have potentially resectable disease, mainly because of the possibility of tumor-related morbid symptoms (eg, pain, lung collapse, bronchial obstruction, hemoptysis) and mortality [10,13]. Prognosis after surgical removal is usually good, but the individual course remains unpredictable [10,13,71,191,193,194].

●Radiation therapy – Some advocate low-dose whole-lung RT for patients with pulmonary metastases who are poor surgical candidates or who decline thoracic surgery, for those whose disease is technically unresectable, or if disease recurs or progresses after surgery [195].

Denosumab for persistently unresectable or metastatic disease — We suggest denosumab rather than other forms of systemic therapy, such as bisphosphonates or chemotherapy, for patients with persistently unresectable or metastatic disease.

The efficacy of denosumab in those with pulmonary metastases has also been demonstrated in various phase II trials, one randomized trial, and other studies [135,137,138,140,196]. Denosumab is also approved by the US Food and Drug Administration (FDA) for treatment of patients whose GCTB cannot be surgically removed or when surgery is likely to result in severe morbidity, such as loss of limbs or joint removal. We typically administer GCTB denosumab at 120 mg subcutaneously every 28 days, with two additional loading doses on days 8 and 15 of the first month. Long-term toxicities of denosumab in patients with GCTB are rare (<5 percent) and include hypophosphatemia, osteonecrosis of the jaw, hypercalcemia, and atypical femur fractures [140]. Additionally, the rate of malignant transformation into sarcoma was low (1 percent) in one study of patients treated with denosumab for over four years [140]. (See 'Neoadjuvant denosumab' above.)

Details regarding the use of neoadjuvant denosumab and the mechanism of action are discussed separately. (See 'Neoadjuvant denosumab' above and 'Histogenesis and molecular pathogenesis' above.)

In a randomized trial of 160 patients with GCTB that was unsalvageable or salvageable but with significant morbidity, denosumab improved four-year cumulative recurrence-free survival and complete response rates (10 versus 2 percent) compared with zolendronic acid [196]. The risk of disease progression was also lower with denosumab relative to zolendronic acid (12.5 versus 15 percent). Tumor response rates, clinical benefit (reducing pain, improved mobility and functional activity), and overall survival were similar between the two treatment arms. Both treatments were well tolerated with different toxicity profiles. Denosumab had higher rates of fatigue and back pain, while zolendronic acid had higher rates of hypocalcemia, flu-like symptoms, and hypotension.

Similarly, in a phase II trial, 37 patients with recurrent, unresectable GCTB (including nine with lung metastases) were treated with denosumab 120 mg subcutaneously every 28 days, with two additional loading doses on days 8 and 15 of the first month [137]. Thirty patients (86 percent) had an objective response to therapy, which was defined as either ≥90 percent elimination of giant cells on histologic evaluation or the absence of radiographic progression of the target lesion up to week 25. There was also sustained suppression of markers of bone turnover, as early as 28 days after the first dose and sustained for the duration of the study, and a reduction in uptake of fluorodeoxyglucose (FDG), suggesting that FDG-positron emission tomography (PET) may be an early and sensitive marker for clinical response in GCTB [197].

Treatment was well tolerated in general. Although adverse events were reported in 33 patients (89 percent), the most common were pain in an extremity (n = 7), back pain (n = 4), or headache (n = 4). Of the five adverse effects of grade 3 or higher, only one was thought to be treatment related (grade 3 increase in human chorionic gonadotropin [hCG] not related to pregnancy).

However, there is scant information on the long-term side effects of denosumab in the GCTB population; adverse effects that should be considered in therapeutic decision making include the following:

●Osteonecrosis of the jaw – As with bisphosphonates, the duration of denosumab therapy influences risk, although at least some data support the view that the risk plateaus between years 2 and 3.

Data on long-term use of denosumab in those with GCTB are available from observational studies. In one report of 97 patients with GCTB, a cohort of 54 patients with unresectable tumors was treated with denosumab for a median of 54 months [135]. Of these patients, five developed osteonecrosis of the jaw (9 percent). Other prolonged treatment toxicities included mild peripheral neuropathy (11 percent), skin rash (9 percent), hypophosphatemia, and atypical femoral fracture (4 percent each).

Meta-analyses of data from randomized clinical studies of denosumab versus bisphosphonates in the general cancer population indicate a slightly but not significantly increased rate of osteonecrosis of the jaw with denosumab (1.7 versus 1.1 percent [198]), although the relative risk may change with longer follow-up of these trials with denosumab. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Denosumab'.)

Long term side effects of denosumab in the neoadjuvant setting are discussed separately. (See 'Neoadjuvant denosumab' above.)

●Malignant transformation – Cases of malignant transformation of giant cell tumors into high-grade sarcoma with denosumab therapy have been reported in patients without previous radiation exposure, at a rate of approximately 1 percent. However, it is not clear whether the rate of transformation is higher than expected for this at-risk population [85,137,139-141,199-202].

Less preferred options — The role of bisphosphonates in those with recurrent or metastatic disease is unclear as many studies were performed in the pre-denosumab era of GCTB therapy. Chemotherapy and interferon alfa-2b are not considered standard approaches given the benign nature of GCTB and the availability of other therapies with better efficacy and toxicity profiles. Corticosteroids may offer some locoregional disease control in select cases.

Bisphosphonates — The role of bisphosphonates for patients with GCTB is not established and further studies are necessary. Preclinical studies suggest that bisphosphonates may be effective in killing the stromal and osteoclast-like cells of GCTB [203,204] and some clinical reports of bisphosphonates in GCTB initially noted some symptomatic benefit and local disease control, sometimes for prolonged periods [204-206]. However, eradication of tumor giant cells has not been observed following preoperative treatment with bisphosphonates [205,207]. In addition, zolendronic acid had inferior recurrence-free survival relative to denosumab in a randomized trial [196]. (See 'Denosumab for persistently unresectable or metastatic disease' above.)

Chemotherapy and interferon alfa-2b — Given the generally benign nature of the disease and the efficacy and tolerability of other forms of treatment, chemotherapy is not generally considered a standard approach, except for truly malignant GCTB. Interferon is also less preferred due to toxicity and limited availability.

●Chemotherapy – Various studies report the use of cytotoxic chemotherapy (ifosfamide, cyclophosphamide, doxorubicin, cisplatin) in unresectable advanced GCTB [28,68,76,208-211] (and, in some cases, for extraosseous tumors [212]), but none are randomized trials.

●Interferon alfa-2b – Interferon alfa-2b has been used for treatment of "aggressive" disease, but it is not widely used because it is associated with significant side effects [213,214] and has limited availability, as the manufacturer has discontinued production. While anecdotal data suggest antitumor activity [13,213,214], in the absence of prospectively conducted studies, the utility of interferon alfa-2b remains unproven, especially in the denosumab era.

Corticosteroids — In the setting of Paget disease with extraskeletal giant cell tumors, there are some data indicating local control with steroids [215,216]. Control of GCTB growth using triamcinolone injected locally into the tumor was also reported to be of benefit in central giant cell granuloma of the mandible [217].

POSTTREATMENT SURVEILLANCE — There is no consensus as to the appropriate posttreatment surveillance strategy for GCTB at any site. Our approach is as follows, which is generally consistent with guidelines from the National Comprehensive Cancer Network (NCCN):

●Physical examination and imaging of the surgical site as clinically indicated (radiograph; computed tomography [CT] with contrast, with or without magnetic resonance imaging [MRI] with contrast).

●Pulmonary imaging with, at minimum, a chest radiograph every six months for two years, then annually thereafter.

We typically image the primary site with radiograph and/or low-dose CT every three months posttreatment, every three to six months for two to three years, and every four to six months through five years, then chest radiographs annually for life. Although some clinicians follow patients for only five years, others have emphasized the need for annual follow-up for life due to the risk of late locoregional recurrence and/or metastatic disease [65]. Hence, annual visits with radiographs of the local site and chest are prudent. However, clinical judgment is needed in tailoring the frequency of posttreatment imaging to individual patients; one of the most important considerations is the utility of further surgical intervention.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone sarcomas".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Giant cell tumor of bone (GCTB) is a benign but locally active or aggressive bone tumor that typically presents as a lytic lesion in the meta-epiphyseal region of the long bones in young adults, usually around the knee. Other relatively common long bone locations include the distal radius, proximal femur, and proximal humerus. (See 'Introduction' above and 'Epidemiology' above and 'Clinical presentation and imaging' above.)

●Localized appendicular tumors – Surgery is the treatment of choice for GCTB arising in the appendicular skeleton. (See 'Management of localized appendicular tumors' above and 'Choice of surgical intervention' above.)

•For most patients with potentially resectable intraosseous lesions (primary or recurrent), we suggest extended intralesional curettage, followed by filling of the cavity with bone cement (polymethylmethacrylate [PMMA]), rather than simple curettage alone (Grade 2C). One notable exception is for tumor involvement of "expendable bones" (eg, proximal fibula or distal ulna), which are typically treated with more extensive en bloc resection. (See 'Intraosseous disease' above.)

•For most patients with extraosseous extension (particularly involving the distal radius or proximal femur), select cases of pathologic fracture (eg, dislocated intra-articular fracture or gross damage to the articular surface), or tumor involvement of expendable bones (eg, proximal fibula or distal ulna), we suggest en bloc resection, with or without reconstruction, rather than curettage (Grade 2C). For those patients where such an approach may result in worsened postoperative functional outcomes, curettage with an adjuvant may be offered as an alternative to more extensive resection. (See 'Extraosseous disease' above.)

•It is not our routine practice to administer denosumab as an adjuvant to intralesional curettage or following more extensive resection for GCTB. Data are limited on the effect of adjuvant denosumab on local recurrences, and this approach remains investigational. (See 'Is there a role for postoperative denosumab?' above.)

●Potentially resectable disease with significant morbidity – For patients with potentially resectable GCTB for whom initial surgery would be associated with functional compromise or significant morbidity, we suggest initial neoadjuvant denosumab followed by resection, rather than proceeding directly to initial resection (Grade 2C). The antitumor benefits of long-term use of denosumab in this setting must be balanced against the potential side effects, including osteonecrosis of the jaw. (See 'Nonsurgical candidates at presentation' above and 'Neoadjuvant denosumab' above.)

●Locally recurrent, potentially resectable disease – For patients with locally recurrent, potentially resectable GCTB of the appendicular skeleton at minor risk of increased morbidity from such disease recurrence, we offer extended intralesional curettage with a local adjuvant to preserve postoperative function. More extensive surgery may be indicated for a second or later recurrence. (See 'Recurrent disease (localized)' above and 'Surgical candidates' above.)

●Locally recurrent, unresectable disease – For patients with unresectable, locally recurrent disease, options include denosumab, radiation therapy (RT), or arterial embolization. These patients should be screened for pulmonary metastases with a chest computed tomography (CT) because local recurrence is accompanied by an increased risk of pulmonary metastases. (See 'Nonsurgical candidates' above.)

●Localized axial tumors

•Sacral tumors – For patients with large, unresectable midline sacral GCTB (eg, no chance of preserving at least one set of sacral nerve roots) or for poor surgical candidates, we offer either denosumab or RT, balancing the risks of exposure to lifelong denosumab with the risks of RT. Arterial embolization is also an alternative option, although data are limited. (See 'Sacral tumors' above.)

•Spinal tumors – For those with spinal GCTB who are surgical candidates, we offer complete surgical resection, particularly if neurologic impairment is evident. For patients with unresectable lesions and with tumors in high-risk locations, we offer denosumab because some patients may have long-term disease control with this approach. (See 'Spinal tumors' above.)

●Unresectable or metastatic disease

•Resectable pulmonary metastases – For patients with surgically resectable pulmonary metastases who are potentially or actively symptomatic, we suggest surgery rather than observation (Grade 2B). However, other experts may offer observation rather than surgery, given the benign nature of the disease, with surgical intervention as clinically indicated. (See 'Management of unresectable or metastatic disease' above and 'Observation versus locoregional therapy for pulmonary metastases' above.)

•Unresectable pulmonary metastases – For patients with unresectable pulmonary metastases, those with resectable disease who decline thoracic surgery, or those who relapse after initial thoracic surgery, we offer either RT or denosumab. (See 'Observation versus locoregional therapy for pulmonary metastases' above.)

•Persistently unresectable or metastatic disease – For patients with persistently unresectable or metastatic disease, we suggest denosumab over other forms of systemic therapy, such as bisphosphonates or chemotherapy (Grade 2C). The long-term effects of denosumab in patients treated for GCTB are rare and may include osteonecrosis of the jaw and malignant transformation into sarcoma. (See 'Denosumab for persistently unresectable or metastatic disease' above and 'Less preferred options' above.)

●Posttreatment surveillance – For patients undergoing posttreatment surveillance, we typically image the primary site with radiograph and/or low-dose CT every three months posttreatment, every three to six months for two to three years, and every four to six months through five years, then radiographs annually for life, due to the risk of late locoregional recurrence and/or metastatic disease. Clinical judgment is needed in tailoring the frequency of posttreatment imaging to individual patients. (See 'Posttreatment surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.