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Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting...
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Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 14964

Special Issue Editors

Prof. Dr. Ramses Forsyth

E-Mail Website
Guest Editor
Department of Pathology, University Hospital Brussels (UZB), Laarbeeklaan 101, 1090 Brussels, Belgium
Interests: bone; neoplasia; extracellular matrix; GCTB
Prof. Dr. Pancras Hogendoorn

E-Mail Website
Guest Editor
Department of Pathology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2300 RC Leiden, The Netherlands
Interests: sarcoma; osteosarcoma; bone and soft tissue tumors;

Special Issue Information

Dear Colleagues,

We are pleased to invite papers on current research and new insights on giant-cell-containing tumors of bone (GCCTB). While these tumors are morphologically characterized by the presence of numerous osteoclastic-like giant cells, GCCTB still reflect a diverse spectrum of entities, each presenting with its own pathobiological and epidemiologic characteristics, clinical behavior, and outcome. GCCTB are among the most difficult bone tumors to diagnose histopathologically, and they provide many pitfalls. Therefore, a close multidisciplinary approach and understanding is needed to ensure an accurate diagnosis and an adequate therapeutic setting and follow-up. As prototypes of this group, giant cell tumors of bone and chondroblastoma have gained huge scientific, and clinical interest because of the recent finding of a H3.3 driver mutation. Next to this, they offer a true opportunity to explore new  experimental models and epigenetic pathways in order to study oncohistonic carcinogenesis in general.

All original research articles and reviews that address GCCTB pathobiologically, diagnostically, clinically, and therapeutically, and related potential opportunities, are warmly welcomed.

We are looking forward to receiving your valuable contributions.

Prof. Dr. Ramses Forsyth
Prof. Dr. Pancras Hogendoorn
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • giant-cell-containing tumors of bone (GCCTB)

  • giant cell tumor of bone (GCTB)
  • giant cell tumor in Paget's disease
  • malignant giant cell tumor
  • giant cell reparative granuloma
  • fibrohistiocytic tumors and lesions
  • chondroblastoma
  • brown tumor
  • non-ossifying fibroma
  • chrondromyxoid fibroma
  • aneurysmal bone cyst
  • langerhans cell histiocytosis
  • osteosarcoma
  • clear cell chondrosarcoma
  • metastatic carcinoma

Published Papers (9 papers)

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Research

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10 pages, 5327 KiB  
Article
Proximal Tibia Tumour Location and Curettage Are Major Risk Factors of Local Recurrence in Giant Cell Tumour of Bone
by Michal Mahdal, Tomáš Tomáš, Vasileios Apostolopoulos, Dagmar Adámková, Peter Múdry, Iva Staniczková Zambo and Lukáš Pazourek
Cancers 2023, 15(18), 4664; https://doi.org/10.3390/cancers15184664 - 21 Sep 2023
Viewed by 933
Abstract
Giant cell tumour of bone (GCTB) is one of the most common local aggressive tumourous lesions with a wide variety of biological behaviour. However, there are no clear indicative criteria when choosing the type of procedure and the complication rates remain high, especially [...] Read more.
Giant cell tumour of bone (GCTB) is one of the most common local aggressive tumourous lesions with a wide variety of biological behaviour. However, there are no clear indicative criteria when choosing the type of procedure and the complication rates remain high, especially in terms of local recurrence. The purpose of the study was to (1) identify the main risk factors for local recurrence, (2) evaluate the recurrence-free survival in dependence on neoadjuvant denosumab use and the type of procedure, and (3) compare the functional outcomes after curettage and en bloc resection. The group included 102 patients with GCTB treated between 2006 and 2020. The mean age of patients was 34.4 years (15–79). The follow-up period was 8.32 years (2–16) on average. Local recurrence occurred in 14 patients (29.8%) who underwent curettage and in 5 patients (10.6%) after en bloc resection. Curettage was shown to be a factor in increasing recurrence rates (OR = 3.64 [95% CI: 1.19–11.15]; p = 0.023). Tibial location was an independent risk factor for local recurrence regardless of the type of surgery (OR = 3.22 [95% CI: 1.09–9.48]; p = 0.026). The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments at five years postoperatively (p = 0.0307). Functional ability and pain as reported by patients at the latest follow-up were superior after curettage compared to resection for upper and lower extremity (mean difference: −4.00 [95% CI: –6.81 to −1.18]; p < 0.001 and mean difference: −5.36 [95% CI: −3.74 to −6.97]; p < 0.001, respectively). Proximal tibia tumour location and curettage were shown to be major risk factors for local recurrence in GCTB regardless of neoadjuvant denosumab treatment. The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments. The functional outcome of patients after curettage was better compared to en bloc resection. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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14 pages, 14462 KiB  
Article
Histomorphometric Analysis of 38 Giant Cell Tumors of Bone after Recurrence as Compared to Changes Following Denosumab Treatment
by Sophia Arndt, Wolfgang Hartmann, András Rókusz, Benedikt Leinauer, Alexandra von Baer, Markus Schultheiss, Jessica Pablik, Hagen Fritzsche, Carolin Mogler, Imre Antal, Daniel Baumhoer, Kevin Mellert, Peter Möller, Miklós Szendrői, Gernot Jundt and Thomas F. E. Barth
Cancers 2023, 15(17), 4249; https://doi.org/10.3390/cancers15174249 - 24 Aug 2023
Cited by 1 | Viewed by 881
Abstract
Giant cell tumor of bone (GCTB) is an osteolytic tumor driven by an H3F3A-mutated mononuclear cell with the accumulation of osteoclastic giant cells. We analyzed tissue from 13 patients with recurrence and 25 patients with denosumab therapy, including two cases of malignant [...] Read more.
Giant cell tumor of bone (GCTB) is an osteolytic tumor driven by an H3F3A-mutated mononuclear cell with the accumulation of osteoclastic giant cells. We analyzed tissue from 13 patients with recurrence and 25 patients with denosumab therapy, including two cases of malignant transformation. We found a decrease in the total number of cells (p = 0.03), but not in the individual cell populations when comparing primary and recurrence. The patients treated with denosumab showed induction of osteoid formation increasing during therapy. The total number of cells was reduced (p < 0.0001) and the number of H3F3A-mutated tumor cells decreased (p = 0.0001), while the H3F3A wild-type population remained stable. The KI-67 proliferation rate dropped from 10% to 1% and Runx2- and SATB2-positive cells were reduced. The two cases of malignant transformation revealed a loss of the H3F3A-mutated cells, while the KI-67 rate increased. Changes in RUNX2 and SATB2 expression were higher in one sarcoma, while in the other RUNX2 was decreased and SATB2-positive cells were completely lost. We conclude that denosumab has a strong impact on the morphology of GCTB. KI-67, RUNX2 and SATB2 expression differed depending on the benign or malignant course of the tumor under denosumab therapy. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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32 pages, 1504 KiB  
Article
Giant Cells of Various Lesions Are Characterised by Different Expression Patterns of HLA-Molecules and Molecules Involved in the Cell Cycle, Bone Metabolism, and Lineage Affiliation: An Immunohistochemical Study with a Review of the Literature
by Vivien Hild, Kevin Mellert, Peter Möller and Thomas F. E. Barth
Cancers 2023, 15(14), 3702; https://doi.org/10.3390/cancers15143702 - 21 Jul 2023
Cited by 1 | Viewed by 1345
Abstract
Giant cells (GCs) are thought to originate from the fusion of monocytic lineage cells and arise amid multiple backgrounds. To compare GCs of different origins, we immunohistochemically characterised the GCs of reactive and neoplastic lesions (n = 47). We studied the expression [...] Read more.
Giant cells (GCs) are thought to originate from the fusion of monocytic lineage cells and arise amid multiple backgrounds. To compare GCs of different origins, we immunohistochemically characterised the GCs of reactive and neoplastic lesions (n = 47). We studied the expression of 15 molecules including HLA class II molecules those relevant to the cell cycle, bone metabolism and lineage affiliation. HLA-DR was detectable in the GCs of sarcoidosis, sarcoid-like lesions, tuberculosis, and foreign body granuloma. Cyclin D1 was expressed by the GCs of neoplastic lesions as well as the GCs of bony callus, fibroid epulis, and brown tumours. While cyclin E was detected in the GCs of all lesions, p16 and p21 showed a heterogeneous expression pattern. RANK was expressed by the GCs of all lesions except sarcoid-like lesions and xanthogranuloma. All GCs were RANK-L-negative, and the GCs of all lesions were osteoprotegerin-positive. Osteonectin was limited to the GCs of chondroblastoma. Osteopontin and TRAP were detected in the GCs of all lesions except xanthogranuloma. RUNX2 was heterogeneously expressed in the reactive and neoplastic cohort. The GCs of all lesions except foreign body granuloma expressed CD68, and all GCs were CD163- and langerin-negative. This profiling points to a functional diversity of GCs despite their similar morphology. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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13 pages, 3760 KiB  
Article
Bioactive Glass Inhibits Tumor Development from Giant Cell Tumor of Bone-Derived Neoplastic Stromal Cells in a Chicken Chorioallantoic Membrane Assay
by Joerg Fellenberg, Sarina Losch, Max R. Marinescu, Birgit Frey, Burkhard Lehner, Marcela Arango-Ospina, Zoya Hadzhieva, Aldo R. Boccaccini and Fabian Westhauser
Cancers 2023, 15(6), 1868; https://doi.org/10.3390/cancers15061868 - 20 Mar 2023
Cited by 1 | Viewed by 1627
Abstract
Tumor recurrence is a major problem during the treatment of giant cell tumors of bone (GCTB). We recently identified tumor cell-specific cytotoxic effects of bioactive glasses (BGs) toward neoplastic stromal cells derived from GCTB tissue (GCTSCs) in vitro. Since these data indicated a [...] Read more.
Tumor recurrence is a major problem during the treatment of giant cell tumors of bone (GCTB). We recently identified tumor cell-specific cytotoxic effects of bioactive glasses (BGs) toward neoplastic stromal cells derived from GCTB tissue (GCTSCs) in vitro. Since these data indicated a promising role of BGs in the adjuvant treatment of GCTBs, we aimed to investigate the transferability of the in vitro data into the more complex in vivo situation in the current study. We first analyzed the cytotoxicity of three different BGs in vitro by WST-1 assay after co-cultivation with primary GCTSC cell lines. The effects of BGs on tumor engraftment and growth were analyzed by chicken chorioallantoic membrane (CAM) assays and subsequent quantification of tumor take rates and tumor volumes. In vitro, all tested BGs displayed a cytotoxic effect on GCTSCs that was dependent on BG composition, concentration, and particle size. Comparable effects could be observed within the in vivo environment resulting in reduced tumor take rates and tumor volumes in BG-treated samples. These data indicate a possible clinical application of BGs in the context of GCTB therapy, mediating a reduction of recurrence rates with the simultaneous promotion of bone regeneration. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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14 pages, 4054 KiB  
Article
Prognostic Value and Quantitative CT Analysis in RANKL Expression of Spinal GCTB in the Denosumab Era: A Machine Learning Approach
by Qizheng Wang, Yongye Chen, Siyuan Qin, Xiaoming Liu, Ke Liu, Peijin Xin, Weili Zhao, Huishu Yuan and Ning Lang
Cancers 2022, 14(21), 5201; https://doi.org/10.3390/cancers14215201 - 23 Oct 2022
Cited by 2 | Viewed by 1525
Abstract
The receptor activator of the nuclear factor kappa B ligand (RANKL) is the therapeutic target of denosumab. In this study, we evaluated whether radiomics signature and machine learning analysis can predict RANKL status in spinal giant cell tumors of bone (GCTB). This retrospective [...] Read more.
The receptor activator of the nuclear factor kappa B ligand (RANKL) is the therapeutic target of denosumab. In this study, we evaluated whether radiomics signature and machine learning analysis can predict RANKL status in spinal giant cell tumors of bone (GCTB). This retrospective study consisted of 107 patients, including a training set (n = 82) and a validation set (n = 25). Kaplan-Meier survival analysis was used to validate the prognostic value of RANKL status. Radiomic feature extraction of three heterogeneous regions (VOIentire, VOIedge, and VOIcore) from pretreatment CT were performed. Followed by feature selection using Selected K Best and least absolute shrinkage and selection operator (LASSO) analysis, three classifiers (random forest (RF), support vector machine, and logistic regression) were used to build models. The area under the curve (AUC), accuracy, F1 score, recall, precision, sensitivity, and specificity were used to evaluate the models’ performance. Classification of 75 patients with eligible follow-up based on RANKL status resulted in a significant difference in progression-free survival (p = 0.035). VOIcore-based RF classifier performs best. Using this model, the AUCs for the training and validation cohorts were 0.880 and 0.766, respectively. In conclusion, a machine learning approach based on CT radiomic features could discriminate prognostically significant RANKL status in spinal GCTB, which may ultimately aid clinical decision-making. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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16 pages, 3719 KiB  
Article
Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic “Stromal” Cells from Giant Cell Tumors of Bone
by Sanne Venneker, Robin van Eenige, Alwine B. Kruisselbrink, Ieva Palubeckaitė, Alice E. Taliento, Inge H. Briaire-de Bruijn, Pancras C. W. Hogendoorn, Michiel A. J. van de Sande, Hans Gelderblom, Hailiang Mei, Judith V. M. G. Bovée and Karoly Szuhai
Cancers 2022, 14(19), 4708; https://doi.org/10.3390/cancers14194708 - 27 Sep 2022
Cited by 6 | Viewed by 1731
Abstract
The neoplastic “stromal” cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. [...] Read more.
The neoplastic “stromal” cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic “stromal” cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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Review

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16 pages, 3864 KiB  
Review
Brown Tumour in Chronic Kidney Disease: Revisiting an Old Disease with a New Perspective
by Djoko Santoso, Mochammad Thaha, Maulana A. Empitu, Ika Nindya Kadariswantiningsih, Satriyo Dwi Suryantoro, Mutiara Rizki Haryati, Decsa Medika Hertanto, Dana Pramudya, Siprianus Ugroseno Yudho Bintoro, Nasronudin Nasronudin, Mochamad Yusuf Alsagaff, Hendri Susilo, Citrawati Dyah Kencono Wungu, Nicolaas C. Budhiparama and Pancras C. W. Hogendoorn
Cancers 2023, 15(16), 4107; https://doi.org/10.3390/cancers15164107 - 15 Aug 2023
Viewed by 1998
Abstract
Osteitis fibrosa cystica (OFC) and Brown Tumours are two related but distinct types of bone lesions that result from the overactivity of osteoclasts and are most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because [...] Read more.
Osteitis fibrosa cystica (OFC) and Brown Tumours are two related but distinct types of bone lesions that result from the overactivity of osteoclasts and are most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because of their rare prevalence and variability in their clinical manifestation. Canonically, OFC and Brown Tumours are caused by secondary hyperparathyroidism in CKD. Recent literature showed that multiple factors, such as hyperactivation of the renin–angiotensin–aldosterone system and chronic inflammation, may also contribute to the occurrence of these diseases through osteoclast activation. Moreover, hotspot KRAS mutations were identified in these lesions, placing them in the spectrum of RAS–MAPK-driven neoplasms, which were until recently thought to be reactive lesions. Some risk factors contributed to the occurrence of OFC and Brown Tumours, such as age, gender, comorbidities, and certain medications. The diagnosis of OFC and Brown Tumours includes clinical symptoms involving chronic bone pain and laboratory findings of hyperparathyroidism. In radiological imaging, the X-ray and Computed tomography (CT) scan could show lytic or multi-lobular cystic alterations. Histologically, both lesions are characterized by clustered osteoclasts in a fibrotic hemorrhagic background. Based on the latest understanding of the mechanism of OFC, this review elaborates on the manifestation, diagnosis, and available therapies that can be leveraged to prevent the occurrence of OFC and Brown Tumours. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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Other

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14 pages, 402 KiB  
Systematic Review
Treatment of Recurrent Giant Cell Tumor of Bones: A Systematic Review
by Charalampos Pitsilos, Panagiotis Givissis, Pericles Papadopoulos and Byron Chalidis
Cancers 2023, 15(13), 3287; https://doi.org/10.3390/cancers15133287 - 22 Jun 2023
Cited by 1 | Viewed by 1822
Abstract
The giant cell tumor of bones (GCTB) is a benign bone tumor with high postoperative recurrence potential. No specific treatment protocol has been developed to date in case of tumor recurrence, and the kind of re-operative surgery depends upon the surgeon’s preferences. The [...] Read more.
The giant cell tumor of bones (GCTB) is a benign bone tumor with high postoperative recurrence potential. No specific treatment protocol has been developed to date in case of tumor recurrence, and the kind of re-operative surgery depends upon the surgeon’s preferences. The aim of this systematic review is to determine the second recurrence rate and the respective functional results of the available treatment options applied to recurrent GCTB. Medline/PubMed and Scopus were searched to identify articles published until March 2023. Twelve studies fulfilled the inclusion criteria, comprising 458 patients suffering from recurrent GCTB. The overall incidence of second recurrence was 20.5%, at a mean interval of 28.8 months after the first surgery, and it was more evident after intralesional curettage (IC) surgery than en-bloc resection (EBR) (p = 0.012). In the IC group of patients, the second recurrence rate was lower and the functional outcome was greater when polymethylmethacrylate cement (PMMAc) was used as an adjuvant instead of bone grafting (p < 0.001 for both parameters). Reconstruction of the created bone defect after EBR with a structural allograft provided a better outcome than prosthesis (p = 0.028). According to this systematic review, EBR (first choice) and IC with PMMAc (second choice) are the best treatment options for recurrent GCTB. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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15 pages, 2241 KiB  
Systematic Review
Global Prevalence and Risk of Local Recurrence Following Cryosurgery of Giant Cell Tumour of Bone: A Meta-Analysis
by Shyful Nizam Sumari, Nor Azman Mat Zin, Wan Faisham Wan Ismail and Md Asiful Islam
Cancers 2022, 14(14), 3338; https://doi.org/10.3390/cancers14143338 - 8 Jul 2022
Cited by 4 | Viewed by 1823
Abstract
The challenge in the surgical treatment of giant cell tumours of bone is the relatively high recurrence rate after curettage alone. The use of a local adjuvant following curettage, on the other hand, has lowered the rate of recurrence. This systematic review and [...] Read more.
The challenge in the surgical treatment of giant cell tumours of bone is the relatively high recurrence rate after curettage alone. The use of a local adjuvant following curettage, on the other hand, has lowered the rate of recurrence. This systematic review and meta-analysis aimed to investigate the prevalence and risk of local recurrence of giant cell tumours of the bone after cryosurgery and the subsequent complications. Web of Science, Scopus, ScienceDirect, PubMed, and Google Scholar were searched to identify articles published until 13 October 2021. A random-effects model was used to examine the pooled prevalence and risk ratio (RR) of local recurrence in patients with giant cell tumours after cryosurgery with 95% confidence intervals (CIs). This study was registered with PROSPERO (CRD42020211620). A total of 1376 articles were identified, of which 38 studies (n = 1373, 46.2% male) were included in the meta-analysis. Following cryosurgery, the pooled prevalence of local recurrence in giant cell tumours was estimated as 13.5% [95% CI: 9.3–17.8, I2 = 63%], where European subjects exhibited the highest prevalence (24.2%). Compared to other local adjuvants. The RR of local recurrence following cryosurgery was 0.85 (95% CI: 0.63–1.17, I2 = 15%), which was not statistically significant compared to other local adjuvants. We found 3.9% fracture, 4.0% infection, 2.1% nerve injury, and 1.5% skin necrosis as the common complications. Based on the sensitivity analyses, this study is robust and reliable. This meta-analysis estimated a low prevalence of local recurrence of giant cell tumours with low complications following cryosurgery. Thus, it can be one of the adjuvant options for treating giant cell tumours. Full article
(This article belongs to the Special Issue Giant-Cell-Containing Tumors of Bone—New Insights into Pathobiology, the Clinical Setting and Targeted Therapies)
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