Introduction

Giant cell tumor of bone (GCTB) is a locally aggressive but typically benign neoplasm that has garnered significant attention in oncology. Although considered to be benign tumors of bone, GCTB has a relatively high recurrence rate, and metastases occur in 1 to 9% of patients.¹

The hallmark of GCTB is the presence of numerous, evenly distributed multinucleated giant cells.² These giant cells resemble osteoclasts and contain up to 50 nuclei. They are interspersed within a stroma of mononuclear and spindle-shaped cells. The mononuclear cells are considered the neoplastic component of GCTBs, driving the tumor’s growth.³

GCTB represents 4-5% of primary malignant and 20% of benign bone tumors. It most commonly affects individuals aged 20-40, with a slight female predominance.¹ The distal femur and proximal tibia are the most frequent sites (50-70%), followed by the distal radius (10-15%), sacrum, spine (2-5% each), and other bones. The tumor’s origin near the growth plate suggests a possible link to bone development.⁴

GCTBs are known for their aggressive nature and high post-treatment recurrence rates. Various factors contribute to the likelihood of recurrence, which can complicate management and treatment strategies. Understanding these risk factors is crucial for improving patient outcomes and tailoring treatment plans. Curettage vs resection: curettage, a common surgical method for GCTB, is associated with higher recurrence rates, approximately 18.4 to 32.4%, compared to en bloc resection, which has a significantly lower recurrence rate of 4.6 to 10.6%.⁵ Tumors located in the proximal tibia and distal radius are more prone to recurrence. The proximal tibia has been identified as an independent risk factor for recurrence, regardless of the surgical method used.⁵ Similarly, the distal radius is frequently associated with soft tissue recurrence,⁶ and the proximal Femur also shows a higher recurrence rate, mainly when treated with curettage.⁷ Younger patients under 30 years old are at a higher risk of recurrence; this may be due to the biological behavior of the tumor in younger individuals.⁸ Soft tissue invasion and pathological fractures at presentation are associated with increased recurrence rates. It has been hypothesized that these factors complicate surgical management and may lead to incomplete tumor removal.⁷ Higher mitotic counts and vascular invasion are significant predictors of recurrence.⁸ Denosumab has been shown to influence recurrence rates. While it is used to reduce tumor size preoperatively, its impact on recurrence is complex and may depend on the surgical method employed.⁵

While these factors are significant, it is important to consider the variability in individual cases. Factors such as tumor size, Campanacci grade, and inflammatory markers have not shown consistent associations with recurrence.⁹ Additionally, the potential for malignant transformation in recurrent cases highlights the importance of vigilant follow-up and management strategies.³

Material and methods

We performed a retrospective analysis of 97 cases of GCTB treated at the Instituto Nacional de Cancerología (INCan) in Mexico City, a leading institution in oncological care, between 2010 and 2023. The inclusion criteria were a confirmed histopathological diagnosis of GCTB, a minimum follow-up of six months, and the availability of complete medical records.

The analysis included epidemiological data, clinical assessments, radiographic and histopathological findings, surgical approaches, the application of local adjuvants, and the administration of denosumab. The study population comprised patients of all age groups with tumors located in the appendicular or axial skeleton, as well as the head and neck regions. The cohort also included individuals who had previously undergone treatment at other healthcare institutions and those presenting with de novo metastatic disease.

Clinical and radiographic assessments were performed during follow-up evaluations using standardized protocols derived from international guidelines.

Results

This analysis included 97 Mexican GCTB patients treated at INCan from 2010 to 2023. The median follow-up duration for these patients was 55 months (IQR 21 to 91 months). The patients are located across the country’s central and southern regions, reflecting a diverse socioeconomic background. Their distances to healthcare facilities vary significantly, with a mean radius of 238 kilometers, ranging from 2 to 2,590 kilometers (Figure 1).

Figure 1: Geographic landscape of Mexicans with giant cell tumor at the Instituto Nacional de Cancerología (N = 97). 

Table 1: summarizes the demographic and histopathological characteristics of the cohort. The group comprised 38 women (39%) and 59 men (61%), with a medium age at diagnosis of 30 years (range 23-39 years). Campanacci stages I and II represented 21% of the cases (n = 21), while Campanacci stage III accounted for 77% (n = 75). The medium tumor size was 8.8 cm (range 6.0-11.0).

Most tumors, accounting for 82% (n = 80), were in the appendicular skeleton. Within this group, the femur was the most frequently affected bone, representing 28% (n = 27) of the cases, followed by the tibia at 22% (n = 21), the radius at 13% (n = 13), and the humerus at 7% (n = 7). Tumors in the axial skeleton comprised 18% of the total cases (n = 17). Among the tumors in the axial skeleton, the most common sites were the sacrum at 5% (n = 5), dorsal spine at 4% (n = 4), and skull bones at 2% (n = 2) (Figure 2). Additionally, 23% (n = 22) of the cases presented with a pathologic fracture, and 10% (n = 10) of patients had lung metastases at the initial staging.

Figure 2: Location of tumors in the axial skeleton. 

Of 97 tumors, 72% (n = 70) were classified as primarily resectable. Surgical interventions were conducted on 83% (n = 81) of the patients, with the following distribution of treatment modalities: intralesional resection combined with local adjuvant therapy for 26% (n = 26), and marginal or wide resection, with or without reconstruction, for 50% (n = 49); while 15% (n = 15) received medical management. Furthermore, one patient (1%) received radiotherapy, while 6% (n = 6) required amputation (Figure 3). The remaining 27% (n = 26) were deemed unresectable due to various factors, including significant surgical morbidity, personal and familial decisions, poor clinical condition, preoperative cytoreduction, and the presence of pulmonary metastases.

Figure 3: Treatments. 

The local recurrence rate among patients who underwent surgical intervention was 15%. As expected, recurrence rates were significantly higher following intralesional and marginal resections compared to wide resections, at 67, 14, and 0%, respectively. Local recurrence was more frequent in the axial skeleton (23%, n = 4) than in the appendicular skeleton (14%, n = 11). Stratification by individual tumor sites revealed recurrence rates of 31% in the radius (4 of 13 cases), 10% in the tibia (2 of 21), and 7% in the femur (2 of 27). No significant associations were found between clinicopathologic characteristics, surgical approach, and distant recurrence.

In the univariate analysis, factors such as age, sex, aneurysmal bone cyst component, tumor extension, neutrophil-to-lymphocyte ratio, prognostic nutritional index, overweight or obesity, neoadjuvant denosumab, and pathological fractures showed no significant correlation with recurrence rates. However, as a group, tumors in the lower extremities were significantly associated with local recurrence (p = 0.036). Table 2 summarizes the univariate analyses and associated factors.

In this cohort, treatment at a high-volume center and local therapy were key determinants of recurrence risk. Patients managed at a high-volume center had a local recurrence rate of 11% (10 of 87) versus 50% (5 of 10) among those initially treated elsewhere (p = 0.001) (Figure 4). Local adjuvant therapy was associated with lower local recurrence (p = 0.002), though the sample size was limited.

Figure 4: Recurrence rates. 

Finally, we analyzed Kaplan-Meier curves (Figure 5) and demonstrated that among the 81 tumors (83%) treated with primary intervention, the median recurrence-free survival was 139 months, with a 100% five-year overall survival rate. Additionally, in patients with de novo lung metastases, the overall survival analysis indicated a median survival of 127 months.

Figure 5: Recurrence-free survival. 

Discussion

GCTB is a rare but locally aggressive tumor primarily affecting young adults. Although it is classified as benign, it poses significant therapeutic challenges due to its potential for local recurrence, pathological fractures, and even distant metastases. Effective management relies on a multidisciplinary approach, with surgical resection as the cornerstone of treatment.¹⁰,¹¹ However, recurrence rates remain highly variable, influenced by factors such as tumor location, surgical technique, and adjuvant therapies.¹²,¹³ This study evaluates the unique characteristics of a Mexican cohort, emphasizing clinicopathological features, geographic disparities, and surgical techniques as critical factors associated with local and distant recurrence.

Incidence rates vary from 1.03 to 1.33 cases per million annually, with recurrence rates reported between 10 and 75%.¹⁴,¹⁵,¹⁶,¹⁷,¹⁸ Intralesional resections, while effective in preserving function, carry a higher risk of recurrence unless combined with adjuvant therapies such as phenol, cryotherapy, or cement augmentation.¹⁰,¹⁷,¹⁹,²⁰ Wang, et al. demonstrated that local recurrence increases the risk of pulmonary metastases, corroborated by our finding that 10% of patients present with lung metastases at diagnosis.¹²,²¹,²²

Lesions in the axial skeleton present unique challenges, with higher recurrence rates and surgical complexities compared to appendicular locations.¹⁵,²³,²⁴ In our cohort, axial lesions exhibited a 23% recurrence rate compared to 14% in appendicular tumors, consistent with reports by Balke et al. skull bone lesions showed a 50% recurrence rate, underscoring the difficulty of achieving clear margins in these locations.¹⁵,¹⁶,²⁵,²⁶,²⁷

Geographic disparities emerged as a significant factor, with patients traveling up to 2,590 kilometers for treatment. Becker et al. found similar disparities in Brazil, highlighting worse outcomes among underserved populations.⁴,¹⁷ Our findings suggest that such disparities likely delay diagnosis and limit access to timely intervention, contributing to more advanced disease stages at presentation. Tsukamoto et al. highlighted that outcomes improve significantly in high-volume centers due to standardized practices rather than surgeons’ expertise. Our findings corroborate this trend, even with a limited cohort initially treated elsewhere.³,²⁸,²⁹,³⁰

Denosumab is pivotal in managing GCTB, particularly as a cytoreductive agent and in the metastatic setting. Targeting the RANKL pathway effectively reduces tumor burden, enhancing the feasibility of surgical resection, especially in cases deemed unresectable or located in anatomically challenging regions. This benefit is particularly relevant given that 23% of our cohort presents with pathological fractures, where denosumab facilitates stabilization and preserves skeletal integrity. Additionally, denosumab demonstrates efficacy in controlling disease progression and minimizing complications from skeletal-related events in patients with pulmonary metastases, observed in 10% of our study population. However, its use introduces surgical challenges due to sclerotic bone formation, as confirmed by our findings, necessitating precise preoperative planning and experienced surgical teams. Despite these limitations, denosumab remains an indispensable component in the multimodal treatment of GCTB, optimizing both local control and systemic outcomes in carefully selected patients.²⁶,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰