Giant Cell Tumor of Bone: A Model for the in Vitro Human Osteoclast Characterization

The in vitro growth pattern of cells obtained from bioptic material of ten patients with giant cell tumor of bone (GCT) was investigated. Cytochemical reactions and monoclonal antibodies raised against macrophage markers were tested on the two histologically identifiable GCT cell populations. Only monoclonal antibody EBM/11 stained both mononuclear and giant cells. EBM/11 positivity and resistance of acid phosphatase to high doses of tartrate strongly suggest that both mononuclear and giant cells belong to the same lineage.

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New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling

Cancers ◽

10.3390/cancers13143543 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3543

Author(s):

Michal Mahdal ◽

Jakub Neradil ◽

Peter Mudry ◽

Silvia Paukovcekova ◽

Iva Staniczkova Zambo ◽

...

Keyword(s):

Growth Factor ◽

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Growth Factor Receptor ◽

Metastatic Potential ◽

Giant Cells ◽

Cell Tumor ◽

Primary Bone Tumor

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy.

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Extracellular Ca2+ sensing is modulated by pH in human osteoclast-like cells in vitro

AJP Cell Physiology ◽

10.1152/ajpcell.1994.267.4.c961 ◽

1994 ◽

Vol 267 (4) ◽

pp. C961-C968 ◽

Cited By ~ 21

Author(s):

M. Grano ◽

R. Faccio ◽

S. Colucci ◽

R. Paniccia ◽

N. Baldini ◽

...

Keyword(s):

Bone Resorption ◽

Giant Cell Tumor ◽

Giant Cell ◽

Apical Membrane ◽

Cell Tumor ◽

Polarized Cells ◽

Human Osteoclast ◽

Intracellular Signal ◽

Isolated Rat

Osteoclasts are polarized cells with a basolateral and an apical membrane exposed to different extracellular Ca2+ ([Ca2+]o) and H+ (pHe) concentrations. Osteoclast bone resorption is inhibited in vitro by increases of [Ca2+]o slightly above physiological levels, detected by a [Ca2+]o sensing causing elevations of the intracellular signal, [Ca2+]i. Nevertheless, during bone resorption the apical membrane is exposed to [Ca2+]o severalfold higher than physiological without apparent inhibition of osteoclast functions. Because pHe facing the apical membrane is acidic, in this single-cell [Ca2+]i and intracellular pH study we addressed the question of whether the responses of human osteoclast-like cells from a giant cell tumor of bone to elevated [Ca2+]o are altered by reducing pHe. We first observed that low pHe stimulated Ca2+ efflux and cell acidification. We then demonstrated that the amplitude of the [Ca2+]o-dependent [Ca2+]i "spikes" is downregulated by low pHe, with approximately 70-fold higher [Ca2+]o required to induce significant responses at pHe 6.0 compared with pHe 7.4. Similar downregulation was observed in authentic freshly isolated rat osteoclasts. Finally, we observed that occupancy of the [Ca2+]o sensing by Ca2+ prompted rapid and transient cell acidification partially counteracted by a Na(+)-dependent amiloride derivative-sensitive H+ transport. These results demonstrate that the cascade of events triggered by activation of the [Ca2+]o sensing is affected by environmental pH and in turn influences cellular H+ transport. Such pH-related features of the [Ca2+] o sensing mechanism might be relevant for the regulation of osteoclast-like function.

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CLINICAL AND MORPHOLOGICAL CORRELATIONS AND HISTOPATHOLOGY OF JOINT DAMAGE IN PATIENTS WITH DIFFUSE-TYPE TENOSYNOVIAL GIANT CELL TUMOR

Wiadomości Lekarskie ◽

10.36740/wlek201912102 ◽

2019 ◽

Vol 72 (12) ◽

Author(s):

Olena O Dyadyk ◽

Anastasiia Hryhorovska

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Size ◽

Giant Cells ◽

Cell Tumor ◽

Multinucleated Giant Cells ◽

Diffuse Type ◽

Association Coefficient ◽

Mean Values ◽

Tenosynovial Giant Cell Tumor

Introduction: Tenosynovial giant cell tumor (TSGCT) (synonym – pigmented villonodular synovitis) – is a rare benign proliferative lesion of the synovial sheath, localized in the joint capsule, bursa or tendon sheath and characterized by locally destructive growth. Depending on the prevalence within the joint elements, the presence of a capsule around the tumor, histophotographic features of cell structure and clinical behavior TSGCT can be divided to localized or diffuse type. The aim of the study was researching of histopathological properties of diffuse-type TSGCT, determine the parameters its morphological indicators and to find out the correlation between these morphological and clinical parameters. Materials and methods: The research material was used biopsy (resect) of pathological lesions from 50 patients who were diagnosed and histologically verified diffuse-type TSGCT. Microscopic examinations of the stained sections and their photo archiving were carried out with use of a Olympus-CX 41 light optical microscope. Group measurable parameters (mean values and Pearson tetrachoric index (association coefficient) were calculated in groups of comparison for morphological and clinical indices of TSGCT. The mean values were compared by Student’s test, P value of ≤0.1 was considered statistically significant. Results:Correlation analysis of indicators that accounted for the pairs of cases «clinic – morphology» revealed the relationships, that had the highest parameters of the association coefficient between such indicators: «presence of villous growths» - «severity of hemosiderosis» (if hypertrophied synovial villi available, with vascular injection and pronounced proliferation of synovial cells, there is also a significant accumulation of hemosiderin pigment); «presence of villous growths» - «type of predominant cellular proliferates» (if cells of TSGCT diffuse type consists of monotonous sheets of stromal cells, with uniform, oval to reniform nuclei, the proliferation of villi in synovial layer is non-distinctive); «presence of nodes» - «kind of stroma» (if nodes predominate, their histological structure is mainly represented by polymorphic clusters of synovitis cells in the form of cells, strands, chains, solid formations, among immature connective tissue with low hyalinosis); «cell size (area, cm²)» - «severity of haemosiderosis» and «cell size (area, cm²)» - «the number of multinucleated giant cells» (there is a pronounced deposition of pigment and accumulation of osteoclast-like multinucleated giant cells type, although usually their number is relatively small compared to the localized type of TSGCT). Conclusions: Morphological parameters, that we have identified, characterize pathological changes in the tissues of TSGCT; careful analysis of the frequency of their occurrence in the different comparison groups made it possible to establish intergroup differences and correlations between individual indicators, which were previously unknown or not obvious. Our study was determine to analyze of incidence rates and correlation relationships, revealed some previously unknown differences and dependencies that are important for understanding the pathogenesis, improvement of diagnosis and prognosis of diffuse-type TSGCT.

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Anti-IL17 antibody Secukinumab therapy is associated with ossification in giant cell tumor of bone: a case report of pathologic similarities and therapeutic potential similar to Denosumab

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04182-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Andrew Chandler ◽

Meredith K. Bartelstein ◽

Tomohiro Fujiwara ◽

Cristina R. Antonescu ◽

John H. Healey ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Giant Cell Tumor ◽

Giant Cell ◽

Therapeutic Potential ◽

Quantitative Polymerase Chain Reaction ◽

Treatment Method ◽

Giant Cells ◽

Cell Tumor ◽

Pcr Analysis ◽

Increased Risk

Abstract Background Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage. Case presentation One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB. Conclusions Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.

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Giant Cell Poor Extra-Articular Diffuse-Type Tenosynovial Giant Cell Tumor With Extensive Desmin Expression: A Potential Diagnostic Pitfall With Cytogenetic Confirmation

International Journal of Surgical Pathology ◽

10.1177/1066896918788678 ◽

2018 ◽

Vol 27 (1) ◽

pp. 59-61

Author(s):

Liurka Lopez ◽

Karen Schoedel ◽

Ivy John

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Mononuclear Cells ◽

Giant Cells ◽

Cell Tumor ◽

Diffuse Type ◽

Tenosynovial Giant Cell Tumor ◽

Diagnostic Pitfall

Diffuse-type tenosynovial giant cell tumor can rarely present as an entirely extra-articular mass, which can be misdiagnosed as a sarcoma especially when giant cells are absent, dominated by large dendritic mononuclear cells, and desmin expression is extensive.

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Giant cell tumor stromal cells: osteoblast lineage-derived cells secrete IL-6 and IL-10 for M2 macrophages polarization

PeerJ ◽

10.7717/peerj.9748 ◽

2020 ◽

Vol 8 ◽

pp. e9748

Author(s):

Kuan Yang ◽

Lihui Bao ◽

Xiaoning He ◽

Wanmin Zhao ◽

Dongdong Fei ◽

...

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Macrophage Polarization ◽

Giant Cells ◽

Interleukin 10 ◽

Cell Tumor ◽

M2 Macrophages ◽

M2 Polarization ◽

Macrophages Polarization

Background The giant cell tumor (GCT) is a benign tumor which consists of three types cells: mononuclear histiocytic cells (MNHCs), multinuclear giant cells (MNGCs), and GCT stromal cells (GCTSCs). Numerous studies claim that GCTSCs have mesenchymal stem cells (MSCs) characters and play an important role in osteoclastogenesis; however, there are no research studies concerning macrophage polarization among GCT, which can be regarded as an ingredient for tumor aggression. Method We tested the effect of GCTSCs from three GCT samples which were collected from patients on proliferation, apoptosis and polarization of macrophage. Result In this article, we verified that GCTSCs expressed MSCs markers and had higher proliferation and relative lower differentiation abilities compared with BMMSCs. What’s more, we found a higher proportion of M2 macrophages among neoplasm. Co-culturing GCTSCs with macrophages resulted in prominent macrophage M2 polarization and increased the release of IL-6 (Interleukin-6) and IL-10 (Interleukin-10)from GCTSCs. In conclusion, GCTSCs, as originating from MSCs, can secret IL-6 and IL-10, which may play a significant role in macrophage M2 polarization.

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Giant Cell Tumor of Soft Parts: A Report of an Equine and a Feline Case

Veterinary Pathology ◽

10.1177/0300985875012005-00609 ◽

1975 ◽

Vol 12 (5-6) ◽

pp. 428-433 ◽

Cited By ~ 23

Author(s):

G. H. Ford ◽

R. N. Empson ◽

C. G. Plopper ◽

P. H. Brown

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Giant Cells ◽

Cell Tumor ◽

Superficial Fascia ◽

Femoral Canal ◽

Malignant Giant Cell Tumor ◽

Ultrastructural Characteristics ◽

Characteristic Features ◽

Multinucleate Giant Cells

Masses removed from the superficial fascia of the jugular groove of a 12-year-old Arabian mare and from the femoral canal of a 7 1/2-year-old female cat appeared to be counterparts of the human malignant giant cell tumor of soft parts, even recapitulating the clinical behavior of the respective subgroups. Histologically, both neoplasms contained the characteristic features of the malignant giant cell tumor of soft parts: large multinucleate giant cells, pleomorphic mononuclear giant cells, histiocytes, fibroblasts and fibrocytes that were sometimes sarcomatous, and foci of hemorrhage and necrosis. Ultrastructural characteristics of the giant cells suggest mesenchymal origin with osteoblastic or chondroblastic differentiation.

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Giant Cell Tumor of Tendon Sheath: Immunohistochemical Study of 20 Cases

Tumori Journal ◽

10.1177/030089169708300514 ◽

1997 ◽

Vol 83 (5) ◽

pp. 841-846 ◽

Cited By ~ 10

Author(s):

Antonio Cavaliere ◽

Angelo Sidoni ◽

Emilio Bucciarelli

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Mononuclear Cells ◽

Neuron Specific Enolase ◽

Synovial Cell ◽

Tendon Sheath ◽

Giant Cells ◽

Cell Tumor ◽

Electron Microscopic ◽

Filament Bundles

Aims and background Giant cell tumor of tendon sheath (GCTTS) is a common tumor occurring on the tendon sheaths of the fingers. The nature of this lesion is still controversial: some researchers consider it a reactive process arising from chronic inflammation while others regard it as a tumor of presumed synovial cell or monocytic macrophage system origin. In an effort to clarify the histogenesis we decided to further investigate the immunophenotypic profile of this tumor. Study design We studied 20 GCTTS of the fingers using a panel of 18 antibodies, 13 monoclonal and 5 polyclonal. Results The immunohistochemical investigation revealed that the mononuclear cells of this lesion can be divided into two groups. The cells of the first and more numerous group were positive for vimentin, PG-M1 and KP1 but also for muscle actin (HHF35 monoclonal antibody) and neuron-specific enolase. A second population of mononuclear cells, usually arranged around the giant cells, were positive for PG-M1, KP1, LCA and occasionally for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Multinucleated giant cells were also positive for KP1, PG-M1 and LCA monoclonal antibodies. A variable but usually weak positivity for al-pha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme was also observed. Conclusions Our results suggest a synovial cell origin for GCTTS and do not support the hypothesis that it could be a neoplasm with a true histiocytic origin. The positivity of some cells for the HHF35 antibody, together with electron microscopic evidence of filament bundles with focal dense bodies, suggests that at least part of the mononuclear cells may have a myofibroblastic differentiation.

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Histomorphometric Analysis of Pre- and Post-Denosumab–Treated Giant Cell Tumor of Bone

International Journal of Surgical Pathology ◽

10.1177/1066896920920716 ◽

2020 ◽

Vol 28 (8) ◽

pp. 859-867

Author(s):

Nasir Ud Din ◽

Masood Umer ◽

Yong-Koo Park

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Mononuclear Cells ◽

Giant Cells ◽

Cell Tumor ◽

P Value ◽

Osteoblastic Activity ◽

Woven Bone ◽

Hematoxylin And Eosin

Context. Denosumab is a monoclonal antibody against RANK ligand. Its administration in giant cell tumor of bone (GCTB) cases results in elimination of giant cells and new bone formation. Neoplastic stromal cells of GCTB harbor mutation of histone 3.3 and have pre-osteoblastic properties and thus express SATB2. Objectives. To (1) analyze histological changes in post-denosumab–treated GCTB, (2) analyze expression of H3.3G34W and SATB2 in pre- and post-denosumab–treated samples, and (3) to discuss why changes occur in the expression of not only H3.3G34W but also SATB2. Materials and Methods. Hematoxylin and eosin slides of 19 cases of denosumab-treated GCTB were reviewed. Immunohistochemical stains H3.3G34W and SATB2 were performed. The number of positive mononuclear cells were counted and graded. Results. Complete absence of osteoclast-like giant cells (OCLGCs) was noted in most cases along with a fibro-osseous component merging with peripheral shell of reactive bone. Irregular trabeculae of woven bone and osteoid with focal osteoblastic rimming was seen. Spindle cells were arranged predominantly in fascicular pattern. Morphometric analysis of H3.3G34W showed a mean of 68.8% positive stromal cells in pretreatment and a mean of 26.9% positive stromal cells in posttreated specimens with a statistically significant P value (.001). Mean percentage of SATB2-positive stromal cells in the pre- and posttreatment specimens was 36.46% and 20.8%, respectively. Conclusions. Our study validates that denosumab treatment results in marked reduction of OCLGCs with increased osteoblastic activity. Decreased expression of H3.3G34W in posttreatment may be a result of decreased antigenicity of neoplastic mononuclear cells. No significant change in SATB2 expression was noted.

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