Central giant cell granulomas of the jaws stromal cells harbour mutations and have osteogenic differentiation capacity, in vivo and in vitro

Luiz, Lucyene Miguita; Souza, Juliana Cristina de; Bastos, Victor Coutinho; Pereira, Núbia Braga; Freitas, Raphaela Alvarenga Braga de; Guimarães, Letícia Martins; Avelar, Gleide Fernandes de; Andrade, Luciana O.; Dutra, Walderez Ornelas; Nunes, Fábio Daumas; Castro, Wagner Henriques; Lacerda, Júlio César Tanos de; Reis, Amanda Maria Sena; Bernardes, Vanessa Fátima; Diniz, Marina Gonçalves; Gomez, Ricardo Santiago; Gomes, Carolina Cavaliéri

doi:10.1111/jop.13274

Cited by 9 publications

(7 citation statements)

References 29 publications

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“…Gomes and colleagues demonstrated that sporadic CGCL of the jaws do not share the H3F3A pGly34Trp or p.Gly34Leu mutations reported in GCT of long bones. These ndings appear to add to the body of evidence that the CGCL of the gnathic bone is distinct and separate from the extragnathic GCT [19].…”

Section: Discussionsupporting

confidence: 55%

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

Lazim,

Gupta,

Mallikarjuna

et al. 2023

Preprint

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Background Central giant cell granuloma (CGCG) is an intraosseous, locally invasive, rare non- neoplastic lesion. Histologically, CGCG is characterized by aggregates of multinucleated giant cells, in a background of hemorrhage and reactive fibrous tissue, infiltrating between the eroded bone trabeculae. As an idiopathic non- neoplastic proliferative lesion, CGCG was first described by Jaffe in 1953. Although intraosseous hemorrhages or trauma are possible mechanisms, still the lesion is of unknown histogenesis and etiology. The mandible is a common location of involvement, and CGCG manifest as unilocular or multilocular radiolucent lesion on X rays. Children and young adults are the population most affected, with slight female preponderance. Methods and Materials: A total of 21 cases of CGCG were diagnosed at the oral pathology/pathology department in Temple University Hospital from 2015–2022. All the cases were evaluated retrospectively by studying the following parameters, age, gender, symptoms, radiographic findings, clinical differential diagnosis and the histological confirmation of the cases as central giant cell granulomas. X- Ray of the mandible and maxilla were the main radiographic technique utilized to help establishing the diagnosis. The paraffin embedded tissue was cut at 5um thickness sections and stained by routine H&E stain. No special histochemical or immunohistochemical stains were used. Results Of the total of 21 cases, nine were males and eleven were females, while a single case was of unknown gender. Age range was 15–76 years, with a mean of 50 years. The mandible was the most common location of involvement (17; 81%), and maxilla was affected less commonly (4 cases; 19%). Many of the CGCG lesions were asymptomatic (13; 62%); eight cases (38%) were symptomatic, and the main manifestations were pain, and fullness of the affected dental region. In a minority of cases, brown tumor (severe hyperparathyroidism) and odontogenic neoplasms, such as ameloblastoma, were suspected clinically and radiographically. The diagnosis of central giant cell granuloma with associated acute and chronic inflammation was confirmed in all the cases. Histological evaluation of the H&E-stained sections was the main diagnostic tool utilized. No special stains or molecular studies were required to establish the final diagnosis. Discussion We have concluded that CGCG is non-neoplastic, with aggressive or non-aggressive behavior, predominantly involving the mandible, with rare cases involving the maxilla. No confirmed association with neoplastic lesion was recognized. The lesions followed an indolent clinical course, and some were associated with impacted teeth. CGCG can mimic neoplastic conditions such as ameloblastoma or localized lesion associated with systemic disorders, for instance hyperparathyroidism (brown tumor).

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Section: Discussionsupporting

confidence: 55%

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

Lazim,

Gupta,

Mallikarjuna

et al. 2023

Preprint

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“…Chrcanovic et al demonstrated that sporadic CGCG of the jaws do not share the H3F3A pGly34Trp or p.Gly34Leu mutations reported in GCT in long bones. These ndings appear to add to the body of evidence that the CGCG of the gnathic bone is distinct and separate from the extragnathic GCT [19,20].…”

Section: Discussionsupporting

confidence: 53%

“…[14][15][16][17][18] Giant cell lesions of the jaws may rarely occur in the setting of RASopathy syndromes such as Noonan syndrome or neuro bromatosis. Recently, CGCG have been recognized as benign neoplasms characterized by Ras/MAPK signaling pathway mutations [19].…”

Section: Discussionmentioning

confidence: 99%

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

Lazim,

Sakshi,

Mallikarjuna

et al. 2024

Preprint

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Background: Central giant cell granuloma (CGCG) presents as a locally invasive, intraosseous anomaly characterized by the accumulation of multinucleated giant cells amidst a matrix of hemorrhage and reactive fibrous tissue, which infiltrate the bone trabeculae. This idiopathic non-neoplastic proliferative lesion primarily affects the mandible, typically appearing as either unilocular or multilocular radiolucencies on X-rays. Although trauma or intraosseous hemorrhages are plausible triggers, the precise histogenesis and etiology remain elusive. CGCG predominantly occurs in children and young adults, with a slight predilection for females. Methods and Materials: A retrospective analysis of 21 cases of central giant cell granuloma (CGCG) diagnosed at the oral pathology/pathology department of Temple University Hospital between 2015 and 2022 was conducted. Each case was evaluated based on various parameters including age, gender, presenting symptoms, radiographic findings, clinical differential diagnosis, and histological confirmation. The primary radiographic technique employed for diagnosis was X-ray imaging of the mandible and maxilla. Histological examination involved the cutting of paraffin-embedded tissue into 5-micrometer-thick sections, which were then stained using routine hematoxylin and eosin (H&E) stain. Notably, no specialized histochemical or immunohistochemical stains were utilized in the evaluation process. Results:Of the total of 21 cases, nine were males and eleven were females, while a single case was of unknown gender. Age range was 15- 76 years, with a mean of 50 years. The mandible was the most common location of involvement (17; 81%), and maxilla was affected less commonly (4 cases; 19%). Many of the CGCG lesions were asymptomatic (13; 62%); eight cases (38%) were symptomatic, and the main manifestations were pain, and fullness of the affected dental region. In a minority of cases, brown tumor (severe hyperparathyroidism) and odontogenic neoplasms, such as ameloblastoma, were suspected clinically and radiographically. The diagnosis of central giant cell granuloma with associated acute and chronic inflammation was confirmed in all the cases. Histological evaluation of the H&E-stained sections was the main diagnostic tool utilized. No special stains or molecular studies were required to establish the final diagnosis. Discussion: Our investigation has determined that CGCG exhibits a non-neoplastic nature, displaying a spectrum of behaviors ranging from aggressive to non-aggressive tendencies. Predominantly observed in the mandible, rare instances of CGCG involvement in the maxilla have also been documented. Importantly, no confirmed association with neoplastic lesions was identified during our analysis. The clinical course of CGCG tends to be indolent, with some cases presenting in association with impacted teeth. It's noteworthy that CGCG can present with features mimicking neoplastic conditions such as ameloblastoma or localized lesions linked to systemic disorders, such as hyperparathyroidism (brown tumor). We have concluded that CGCG is non-neoplastic, with aggressive or non-aggressive behavior, predominantly involving the mandible, with rare cases involving the maxilla. No confirmed association with neoplastic lesions was recognized. The lesions followed an indolent clinical course, and some were associated with impacted teeth. CGCG can mimic neoplastic conditions such as ameloblastoma or a localized lesion associated with systemic disorders, for instance hyperparathyroidism (brown tumor).

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“…Sporadic GCG is characterised by somatic, heterozygous, gain‐of‐function KRAS , FGFR1 , and TRPV4 mutations, which were detected in 72% (42/58) of cases [ 8 ]; specifically, KRAS p.G12D/A, p.G13D, p.A146V/P, p.V14L, p.L19F, and p.G10E mutations, FGFR1 p.N330I and p.C381R, and TRPV4 p.M713V/I mutations, with the latter exclusively detected in central lesions [ 8 ]. Such mutations are restricted to the mononuclear cells of the lesions [ 34 ], and converge to activation of MAPK/ERK signalling pathway [ 8 ]. No other pathogenic recurrent mutation could be identified in the remaining 30% of ‘triple wild‐type’ cases [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell‐rich histological mimics

Guimarães

Baumhoer

Andrei

et al. 2023

The Journal of Pathology CR

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Sporadic giant cell granulomas (GCGs) of the jaws and cherubism‐associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell‐rich lesions, including non‐ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell‐rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell‐rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) GCG, cherubism (n = 6), NOF (n = 10), ABC (n = 16), GCTB (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer‐associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism‐associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell‐rich mimics (NOF, ABC, GCTB, and chondroblastoma).

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Central giant cell granulomas of the jaws stromal cells harbour mutations and have osteogenic differentiation capacity, in vivo and in vitro

Cited by 9 publications

References 29 publications

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

Central Giant Cell Granuloma of the Mandible and Maxilla; A Clinicopathological Study of 21 cases

DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell‐rich histological mimics

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