Management and surveillance of metastatic giant cell tumour of bone

Introduction

Giant cell tumour of bone (GCTB) is classified as locally aggressive primary bone tumour [1].

The most common primary tumour sites are meta-epiphyseal regions of long bones, typically the knee joint [2–5]. In the United Kingdom, ≥50 cases of GCTB are diagnosed annually, making up 4%–5% of all primary bone tumours [1, 6]. GCTB has a female to male ratio of between 1.3 and 1.5 to 1, mostly affecting patients aged 20–45. Most present with pain and bone/joint swelling or pathological fracture [7, 8].

Surgery, namely curative resection, is the indicated management [9] and may be in combination with targeted systemic therapy with Denosumab. The indications for denosumab are high risk patients such as those with locally advanced disease, local recurrence, or metastasis. Denosumab has known side effects of arthralgia, fatigue, hypocalcaemia, and rarely osteonecrosis [10, 11]. Surgical treatment varies from curettage and cementoplasty to bone/joint resection and limb reconstruction [12]. Other adjuvant therapies have been used in the past, namely bone grafting, radiotherapy, phenolisation, liquid nitrogen and hydrogen peroxide [13–17].

Typically, the patient undergoes image guided biopsy for histological diagnosis. Macroscopically, the tumour is haemorrhagic and friable, slightly brownish or red-tan. There may be extensive cortical destruction, and a soft tissue component. Microscopic histological analysis shows a giant cell rich lesion within bone which is composed of three cell types, neoplastic mononuclear stromal cells admixed with macrophages and osteoclast-like giant cells [1, 18, 19] (Figure 1). These three cell types interact with each other via the RANKL-RANK axis and other mechanisms leading to tumour formation. The neoplastic mononuclear stromal cells carry a mutation in the H3F3A gene which, together with the H3F3B gene, encodes the histone protein H3.3 involved in epigenetic regulation of DNA expression. The vast majority of these mutations is a glycine 34 to tryptophan (G34W) substitution [20] with a minor subset (<5%) carrying other H3F3A mutations [21]. The mutated protein is expressed in the nucleus of the neoplastic mononuclear stromal cells, and is highly specific for GCTB (Figure 2). The G34W mutation acts via epigenetic regulatory pathways to modulate secretion of factors, including RANK-ligand, which is expressed by the neoplastic cells. This molecule plays a key role in governing bone metabolism and remodelling and promotes differentiation of osteoclasts resulting in the increased aggressive osteolysis characteristic of GCTB [22]. The discovery of the involvement of the RANK-RANKL signalling pathway has led to treatment of GCTB with RANK inhibitors, such as the human monoclonal antibody Denosumab which binds to RANK and so blocks osteolysis, inhibits tumour growth and helps restore bone density [23].

Figure 1. Microscopic appearance of GCTB (Haematoxylin-eosin stain × 10 mag).

Figure 2. Strong diffuse positive nuclear expression of H3.3G34W immunohistochemical marker by the mononuclear component of giant cell tumour of bone. Giant cells are negative.

There is a significant risk of local recurrence (LR) with GCTB, resulting in patients often requiring further surgery with increased morbidity. The incidence of post-surgical LR in GCTB vary from 0%–56% reported (Table 1).

Table 1. Reported rates of GCTB local recurrence in literature.

Although viewed as a locally aggressive benign tumour, GCTB has metastatic pulmonary potential, [41–43]. GCTB pulmonary metastasis (PM) rates are reported as 0%–8% (Table 2).

Table 2. Reported rates of metastatic disease in literature.

Rarely, the tumour can undergo a malignant transformation and is classified as either primary or more commonly secondary malignant GCTBs, the latter as a result of radiotherapy [43, 53–57].

Metastatic disease is viewed as having a benign course [58, 59], however, is associated with higher mortality [36, 47, 60]. With PM, there is risk of progressive respiratory disease and death [37, 50]. As such, recognition and monitoring of PM through standardised surveillance is essential. Management of PM requires surveillance for cardiothoracic surgical management with/without neoadjuvant therapy [43, 54, 61].

To identify occult and metastatic pulmonary disease, patients are routinely followed up with surveillance scanning of extremity and thoracic imaging with PET/CT [36, 52, 62, 63].

LR is known to be an independent risk factor for PM, with other known risk factors namely, primary tumour site, patient age, Campanacci grade, modality of surgical treatment, and local site radiation [36, 48–52].

The primary aim of this study was to determine the true incidence of PM and current surveillance protocols. This would then be used to create recommendations on national surveillance protocols for this unpredictable disease.

Methods

A retrospective audit looking at GCTB patient outcomes identified from the Oxford Sarcoma Registry was performed. The study was registered in the Oxford University Hospitals audit system, receiving ethical approval from the local research ethics committee, reference number 7,605. The study was preformed in accordance with the ethical standards as described in the 1964 Declaration of Helsinki. All patients were diagnosed and treated at Oxford University Hospitals NHS Foundation Trust, and consent was obtained for treatment. As part of the Oxford University Hospitals consent process, all patients consented to their data being used for research and publication purposes. All patient data was anonymised.

Patient records were searched between January 2014 to October 2023. 170 histopathology records were identified, of which 126 were individual patients. The inclusion criterion was histological confirmation of primary GTCB. Exclusion criteria were incomplete medical, imaging or pathology records, referral for a secondary histopathological multidisciplinary team opinion for diagnosis, and histopathological diagnosis of pathology other than primary giant cell tumour of bone on repeat histology.

Of note, three cases with PM were excluded, as they originally showed histological features of GCTB, but diagnosis was changed to osteosarcoma giant cell variant on subsequent sample histopathological review. 43 patients were excluded, leaving 83 for analysis (Figure 3).

Figure 3. Flowchart showing study design including inclusion/exclusion criteria.

The clinical data collected included patient demographics, correlated radiopathology imaging, detailed panelled histology, site of primary tumour, type of surgical and systemic treatment, and LR.

Criteria for diagnosis of PM were either a histological confirmation or enlarging pulmonary nodules on at least two consecutive dedicated CT scans.

Metastatic surveillance protocols were collated from United Kingdom and international bone tumour centres for comparison of surveillance for PM. Birmingham United Kingdom, Newcastle United Kingdom, Oswestry United Kingdom, Aberdeen United Kingdom, Glasgow United Kingdom, Leiden Netherlands, and Perth Australia were asked their current local protocols for surveillance of GCTB.

Statistical analysis

Patient and tumour variables which included gender, age, location of primary tumour, soft tissue invasion of primary tumour, pathological fracture from primary tumour, denosumab therapy prior to diagnosis of PM if applicable, type of surgery, and LR, were collected and analysed as possible risk factors for PM using univariate and multivariate logistic regression statistical analysis in R 4.3.1.

Results

Mean patient age at presentation was 36.4 (range 15–81). Mean follow up time was 44.0 months (range 0–130).

All patients were discussed at regional bone tumour MDT for recommendation of treatment. 77 (93.9%) patients were treated surgically, one treated non operatively with denosumab to good effect, two deemed unfit for surgery and died within 1 year of presentation, and three were being treated with neoadjuvant denosumab at time of data collection. Primary surgical treatment included curettage, excision with reconstruction, or excision followed by joint arthroplasty. Surgical treatment of recurrent disease included the listed options and amputation. Considerations for choice of treatment included location of primary disease, radiological appearance, periosteal and/or soft tissue invasion, and options for surgical reconstruction.

Metastatic disease occurred in eight (9.6%) patients and all metastases were pulmonary. One patient had metastatic disease at diagnosis, seven were identified at follow-up between 2 and 42 months (mean = 20.6) after presentation. Of the eight patients with PM, two were confirmed histologically after one underwent surgery for metastasectomy and one had biopsy, six diagnosed through CT/PET imaging (Table 3).

Table 3. Summary of characteristics of patient demographics, pulmonary metastases, primary tumour, primary surgical treatment, and denosumab treatment.

Of the two diagnosed histologically, the one diagnosed on biopsy showed partial fibrosis and relatively large number of giant cells on histology review, which could indicate effect to denosumab treatment. The one treated with metastasectomy showed a more convincing denosumab treatment effect in the form of fibrosis and bone formation, and Giant cells had disappeared.

Of the patients with PM, three (37.5%) died (between 6 and 12 months after confirmed PM), five alive with stable disease. 35 (42.2%) of all 83 patients were treated with denosumab as per MDT recommendation. Seven patients (87.5%) with PM were treated with denosumab (three before, four after pulmonary diagnosis) (Table 4). No patients with PM had radiotherapy.

Table 4. Results from the 8 patients with metastatic chest disease. Primary tumour site, time to pulmonary disease from GCTB diagnosis, local recurrence free survival, whether they had systemic treatment, survival after pulmonary disease, gender, and age at GCTB diagnosis. DX, diagnosis; Tx, treatment, pul. disease, pulmonary disease.

18 patients (21.7%) had LR, of which 16 (88.9%) were treated with denosumab (nine treated before diagnosis of recurrence and seven after). Five (62.5%) of the eight patients with PM had LR and all required surgery of recurrence.

One patient from all 83 in the study had primary malignant GCTB at time of diagnosis, and that patient developed PM.

Statistical analysis showed that LR was the only significant risk factor for PM, on both univariate and multivariate logistic regression analysis (Table 5).

Table 5. Statistical analysis of patient variables looking at risk factors for chest disease.

Differences between surveillance protocols across specialist sarcoma centres were found. All follow-up protocols are between 5 and 10 years (Table 6).

Table 6. GCTB follow-up and surveillance protocols from different sarcoma centres.

Discussion

GCTB is an unpredictable disease and whilst most cases have a clinically benign course, there is a risk of progressive and latent PM. The results of this study demonstrate PM rate of 9.6%, suggesting that metastasis rate of GCTB to the lungs is higher than reported from historical data. This may be explained partly by the advancements in 3-D imaging, either thin section CT or PET scan, which can identify small volume disease not evident on standard chest x-ray. The risk of latent and progressive disease is a risk of aggressive and fatal PM, so would necessitate CT/PET at presentation and follow-up.

Treatment options for PM include observation and symptomatic treatment, metastasectomy, denosumab, chemotherapy, and radiotherapy. The decision of treatment options is complex and based off MDT discussion, taking into account patient fitness for surgery or systemic treatment, and aggressiveness of disease [43, 46].

62.5% of patients with PM had LR, and analysis showed LR was a statistically significant risk factor for PM, in keeping with current literature.

Therefore, when LR is found, as there is restaging of limb recurrence with MRI, the chest would need careful assessment with CT and/or PET rather than chest x-ray imaging.

Further assessment of the statistical analysis shows that the other patient and tumour variables tested were not statistically significant risk factors for PM, and some of the 95% confidence intervals were very wide, more so on multivariate analysis. This is likely to be due to the relatively small data set.

In this review, 37.5% of patients with PM have died within 12 months of radiological diagnosis of PM, showing that when GCTB does metastasise, it is often unstable and carries a high morbidity and mortality rate. Figure 4 shows imaging of a patient with small volume primary GCTB of the proximal phalanx with secondary aggressive PM found on x-ray and staging CT.

Figure 4. Imaging of GCTB from one of the patients. (A) – X-ray right middle finger 24/09/2018, of primary GCTB tumour. (B) – CT chest, soft tissue window 13/05/2020, showing pulmonary metastatic spread, (C) – X-ray chest 24/08/2020, showing metastatic spread.

Histologically with GCTB it is difficult to predict the risk of metastatic disease. In terms of the histological diagnosis of GCTB, the mutant histone protein H3.3G34W can now be reliably detected in the neoplastic stromal cell population by immunohistochemistry and it serves as a highly specific surrogate marker for this tumour [64]. Expression of the mutant protein is not detected in osteoclasts or their precursors, or by other giant cell rich lesions that mimic GCTB [64]. This marker is often preserved with malignant transformation. In those cases where it is absent, it is proposed that the H3F3AG34W mutation is lost during clonal evolution of the tumour [65].

Three patients initially included, were subsequently excluded when review of their histology changed diagnosis from GCTB to metastatic osteosarcoma. These were tested for H3.3G34W through immunochemistry. Two of these were negative for H3.3G34W, one was positive for the marker. Osteosarcoma can be positive for H3.3G34W in 2.85% of cases [66] and there was no residual benign GCTB areas on histopathological review in this case.

Although the much rarer, primary and secondary malignant giant cell tumours show clear morphological and gene expression correlates reflecting sarcomatous transformation it has proved difficult to pinpoint histological markers that may indicate the metastatic potential of clinically benign cases of GCTB. Morphologically, malignant GCTB have an admixed sarcomatous component, decreased numbers of osteoclast-like giant cells and overt nuclear atypia in neoplastic stromal cells as well as multinucleated giant cells. Gong et al [60] showed in cases of primary and secondary malignant GCTB that expression of p53 and the proliferation marker Ki-67 is increased. Other studies have identified a subset of giant cell tumours which express high levels of beta-HCG, likely a para-neoplastic phenomenon, and it has been suggested markedly elevated beta-hCG expression and secretion may carry a worse prognosis [64].

In contrast, prognostic histological markers for clinically benign GCTB have proved elusive and it remains difficult to predict the behaviour of these tumours at presentation. Antal et al described a technique using smear cytophotometry and proliferation activity by Ki-67 MIB immunohistochemistry to assess DNA ploidy as a possible prognostic marker [67]. Although it has been reported that Ki-67 levels can increase during repeated recurrences [68], studies have not found a significance difference in Ki67, p53, p63, cyclin D1 or Bcl-2 expression between patients who develop PM and LR and those that did not [69, 70]. However, recent molecular studies are more encouraging [71], and multiplex gene analysis methods have suggested that MDM2, IGF1, STAT1 and the GTPase family member RAC1 may be associated with GCTB recurrence [72], raising the possibility that these could be used as markers in the future. Furthermore, gene expression studies show increased LR rates for GCTB are associated with higher levels of expression of the immunomodulatory gene PDL-1 and altered expression of a subset of immuno-system related genes [73] and this may be an area to explore further in identifying prognostic factors for this unpredictable tumour.

Pulmonary metastases require close monitoring with PET and CT scanning and MDT-led treatment decision on metastasectomy surgery with considered adjuvant systemic therapy.

Main limitations to this study include data collection from a single centre and a relatively small data set. However, this has been performed at a specialised unit with experience in managing this unpredictable primary bone tumour. To further validate the data presented from this single unit study, it would further require a multi-centre study of surveillance of GCTB and PM disease.

There is currently no national, or international consensus on surveillance of GCTB, as shown by the variations in protocols between the sarcoma centres described in Table 5. It has been previously suggested that GCTB warrants strict follow-up due to the risk of GCTB malignant transformation and metastatic spread which although rare, carries significant morbidity and mortality.

We would recommend baseline CT chest or PET-CT at diagnosis, with a follow-up CT chest 6 months after surgery or if there is evidence of LR at primary site. Then three monthly chest x-ray up to 2 years, six monthly from 2–5 years, annually from 5–10 years. If PM found, CT chest/PET and MDT review with cardiothoracics for management of resectable disease. We would recommend a national collaboration for a surveillance protocol.

Conclusion

High incidence of PM of >9% was observed in this study, which is higher than reported historically. This result suggests that more rigorous chest surveillance is required with CT chest and/or PET CT at diagnosis and at six-month follow-up with surveillance for 5 years for PM and LR which notably remains a significant risk factor for PM. Further steps are needed to identify markers for malignant transformation potential.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

The study was registered in the Oxford University Hospitals audit system, receiving ethical approval from the local research ethics committee, reference number 7605. The study was preformed in accordance with the ethical standards as described in the 1964 Declaration of Helsinki. All patients were diagnosed and treated at Oxford University Hospitals NHS Foundation Trust, and consent was obtained for treatment. As part of the Oxford University Hospitals consent process, all patients consented to their data being used for research and publication purposes. All patient data was anonymised.

Author contributions

DF and JK performed data collection and analysis, and DF, JK, and CG performed results interpretation. All authors contributed to the article and approved the submitted version.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

The authors would like to thank members of the Oxford Sarcoma Team who contributed to this study; Miss Harriet Branford-White, Professor Nicholas Athanasou, Dr Sarah Pratap. Also colleagues from international institutions for their help; Miss Liz Van Der Heijden from the Leiden Hospital, Netherlands, and Professor David Wood and Professor Richard Carey from University of Western Australia.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References