Asunto(s)
Enfermedades del Tejido Conjuntivo , Granuloma de Células Gigantes , Mucinosis , Enfermedades de la Piel , Humanos , Granuloma de Células Gigantes/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Enfermedades de la Piel/genética , Piel , Mucinosis/diagnóstico , Mucinosis/genéticaRESUMEN
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).
Asunto(s)
Neoplasias Óseas , Querubismo , Condroblastoma , Tumor Óseo de Células Gigantes , Granuloma de Células Gigantes , Humanos , Querubismo/diagnóstico , Querubismo/genética , Querubismo/patología , Granuloma de Células Gigantes/diagnóstico , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/patología , Condroblastoma/diagnóstico , Condroblastoma/genética , Condroblastoma/patología , Metilación de ADN , Células Gigantes/patología , Tumor Óseo de Células Gigantes/diagnóstico , Tumor Óseo de Células Gigantes/genética , Tumor Óseo de Células Gigantes/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Maxilares/patologíaRESUMEN
Sporadic central giant cell granulomas of the jaws (GCGJ) are often solitary lesions, characterized by KRAS, FGFR1, and TRPV4 somatic mutations. Multifocal lesions may occur and are associated with hyperparathyroidism or underlying syndromes such as cherubism, which is marked by SH3BP2 mutations, and RASopathies, which are caused by mutations in the FGFR-RAS-RAF-MEK-ERK signaling cascade. The diagnosis of multiple GCGJ can be challenging. The present case reports a 14-year-old boy with multiple central GCGJ and no obvious syndromic trait. Sanger sequencing-based analysis revealed wild-type sequences for SH3BP2 (exon 9), KRAS (exons 2-4), and FGFR1 (exons 9 and 10) genes. A rare TRPV4 somatic mutation (p.Val708Met) was detected in the lesion on the right side of the mandible, whereas the other tumor and the normal oral mucosa revealed wild-type TRPV4 sequences. This report expands the spectrum of TRPV4 somatic mutations in central GCGJ.
Asunto(s)
Granuloma de Células Gigantes , Masculino , Humanos , Adolescente , Granuloma de Células Gigantes/genética , Canales Catiónicos TRPV/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación/genética , Maxilares/patologíaRESUMEN
Central giant cell granulomas (CGCG) are rare intraosseous osteolytic lesions of uncertain aetiology. Despite the benign nature of this neoplasia, the lesions can rapidly grow and become large, painful, invasive, and destructive. The identification of molecular drivers could help in the selection of targeted therapies for specific cases. TRPV4, KRAS and FGFR1 mutations have been associated with these lesions but no correlation between the mutations and patient features was observed so far. In this study, we analysed 17 CGCG cases of an Italian cohort and identified an interesting and significant (p=0.0021) correlation between FGFR1 mutations and age. In detail, FGFR1 mutations were observed frequently and exclusively in CGCG from young (<18 years old) patients (4/5 lesions, 80%). Furthermore, the combination between ours and previously published data confirmed a significant difference in the frequency of FGFR1 mutations in CGCG from patients younger than 18 years at the time of diagnosis (9/23 lesions, 39%) when compared to older patients (1/31 lesions, 0.03%; p=0.0011), thus corroborating our observation in a cohort of 54 patients. FGFR1 variants in young CGCG patients could favour fast lesion growth, implying that they seek medical attention earlier. Our observation might help prioritise candidates for FGFR1 testing, thus opening treatment options with FGFR inhibitors.
Asunto(s)
Granuloma de Células Gigantes , Humanos , Adolescente , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/diagnóstico , Granuloma de Células Gigantes/patología , Tasa de Mutación , Mutación , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Central giant cell granuloma (CGCG) is a rare disease characterized by sporadic, benign, intraosseous mandibular lesions of unknown etiology. Histologically, these lesions are indistinguishable from brown tumors of hyperparathyroidism and cherubism, and occasionally have been associated with different syndromes raising a question for genetic etiology. The CGCG has varied presentation ranging from nonaggressive and indolent to aggressive, destructive, and recurrent, often posing diagnostic and therapeutic challenges. Herein, we present the first case of a 10-year-old boy with CGCG and 16p13.11 microdeletion syndrome, highlight the diagnostic challenges inherent to this heterogeneous disorder, and discuss the genetics and treatment approaches of these complex lesions.
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Granuloma de Células Gigantes , Niño , Granuloma de Células Gigantes/diagnóstico , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/patología , Humanos , Masculino , Enfermedades RarasRESUMEN
Brown tumors are rare and generally self-limiting mass lesions of bone occurring in the context of hyperparathyroidism. Although commonly regarded as endocrine-driven tumor-like lesions, we detected pathogenic hotspot KRAS mutations in 10/16 brown tumors (62%) with similar frequencies found in cases affecting the peripheral and axial skeleton. Pathogenic mutations in other driver genes of the RAS-MAPK pathway were not identified. Our findings suggest brown tumors to represent true neoplasms driven by the activation of the RAS-MAPK signaling pathway. The frequent regression of brown tumors after normalization of hyperparathyroidism points to a second hit mediated by endocrine stimulation to be required for tumor development. Our findings underline the pathogenic relation of brown tumors to nonossifying fibroma and giant cell granuloma of the jaws which both appear histologically similar to brown tumors and are also driven by RAS-MAPK signaling pathway activation.
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Fibroma , Granuloma de Células Gigantes , Hiperparatiroidismo , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/patología , Humanos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas. METHODS: Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws. The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations. RESULTS: Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups. CONCLUSION: Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.
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Granuloma de Células Gigantes , Canales Catiónicos TRPV , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/metabolismo , Humanos , Maxilares/metabolismo , Maxilares/patología , Metabolómica , Mutación , Proteómica , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Central giant cell granulomas (CGCG) of the jaws are osteolytic lesions that may behave aggressively and respond poorly to surgery. Microscopically, in addition to giant cells, there is a mononuclear cell population composed of macrophage/monocytic cells and spindle-shaped cells of mesenchymal origin. Seventy two percent of these tumours harbour mutually exclusive TRPV4, KRAS and FGFR1 mutations. We aimed to assess the mutational status of mononuclear and giant cells and the osteogenic potential of stromal cells in vitro and in vivo. METHODS AND RESULTS: We screened CGCG for signature mutations and used laser-capture microdissection to demonstrate that the mutations are restricted to the mononuclear cells. Additionally, we established CGCG primary cell culture and observed that the cells retained the mutations throughout passages. By flow cytometry, we observed predominance of CD14- CD51- CD61- cells, consistent with the expected profile for stromal cells. Considering the mesenchymal origin of stromal cells, we assessed the osteogenic differentiation potential of CGCG cells in culture by cytochemistry (von Kossa and alizarin red staining), alkaline phosphatase (ALP) activity assay and gene expression of osteogenic markers. CGCG cells presented self-capacity to increase ALP levels in a time-dependent manner and under osteogenic induction presented increasing number of calcium deposits, and overall higher expression of osteocalcin, RUNX2, ALPL and osteopontin than cells without osteogenic induction. A patient-derived xenograft model for CGCG was established, and osteoid material deposition was observed. CONCLUSION: Collectively, the results confirm that the signature mutations are restricted to stromal cells in CGCG, and the in vitro and in vivo results support that these cells have the capacity to differentiate into osteoblasts, in line with the bone formation often observed in the stroma of these lesions.
Asunto(s)
Granuloma de Células Gigantes , Células Madre Mesenquimatosas , Fosfatasa Alcalina , Diferenciación Celular , Células Cultivadas , Granuloma de Células Gigantes/genética , Humanos , Maxilares , Mutación , Osteogénesis/genética , Células del EstromaRESUMEN
Giant cell granulomas are enigmatic lesions of the oral cavity characterised by a peculiar combined proliferation of mononuclear and multinucleated giant cells in a mesenchymal stromal background. Central and peripheral giant cell granulomas may have similar pathogenesis and histology but differ in their location and biological behaviour. It is important to differentiate them from other giant cell lesions that can occur in the oral cavity, such as giant cell tumour of the bone, aneurysmal bone cyst, brown tumour of hyperparathyroidism, and giant cell lesions of Ramon syndrome, Noonan syndrome, neurofibromatosis and Jaffe-Campanacci syndrome. A recent insight into their molecular genetics and pathogenesis, with identification of KRAS, FGFR1 and TRPV4 mutations, allows for better diagnostic differentiation and opens the door to the use of pathway inhibitors in the treatment of recurrent or dysmorphic lesions. In this review, we provide an updated summary of the clinical and pathological features of oral cavity giant cell granulomas that help with their precise diagnosis and management.
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Proliferación Celular , Células Gigantes/patología , Granuloma de Células Gigantes/patología , Enfermedades de la Boca/patología , Boca/patología , Adolescente , Adulto , Anciano , Biopsia , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Células Gigantes/inmunología , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/inmunología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Boca/inmunología , Enfermedades de la Boca/genética , Enfermedades de la Boca/inmunología , Mutación , Fenotipo , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
The aim of this case report was to detail diagnosis and therapy in a case of implant-associated peripheral giant cell granuloma (IA-PGCG) of the jaw. Case Report: The 41-year-old female attended the outpatient clinic for treatment of recurrent mandibular IA-PGCG. The lesion was excised and the defect was closed with a connective tissue graft of the palate. Healing of oral defects was uneventful, and no local recurrence has occurred during a follow-up of 7 months. Genetic examination of the lesion identified a somatic mutation in KRAS. Conclusion: The lesions are assessed as reactive-inflammatory changes in the mucous membrane of the oral cavity. The cause of the lesion is unknown. KRAS mutations are commonly found in various cancer tissues, but also in germline and mosaic RASopathies. Recently, KRAS mutations have been identified in several IA-PGCG. The clinical course of a frequently locally recurring lesion gives rise to the assumption that lesions of this type show characteristics known in benign neoplasms.
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Granuloma de Células Gigantes , Adulto , Tejido Conectivo , Femenino , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/cirugía , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
The solid variant of aneurysmal bone cyst (SVABC) is very uncommon and frequently misdiagnosed. We reevaluated and summarized the clinicopathologic features of 17 SVABCs and further discussed the use of this nomenclature to differ SVABCs from extragnathic giant cell reparative granuloma (GCRG) in the setting of the USP6 rearrangement era. The immunohistochemical markers included α-SMA, SATB2, AE1/AE3, Ki67, S100, CD68 and P63. USP-6 status was detected by fluorescence in situ hybridization using a break-apart probe. The 17 patients with SVABCs comprised 10 males and 7 females ranging in age from 4 to 70 years. The involved locations included the long bone (n = 11), hand (n = 4), rib (n = 1) and vertebra (n = 1). The lesions were characterized by proliferated spindle cells with scattered giant cells and hemorrhages with variable positive α-SMA, SATB2, CD68 and Ki-67 expression. All patients had USP6 rearrangements without H3F3A glycine 34 mutations. Our study reveals that SVABC shares similar clinical and histologic features with other bone lesions, which may lead to an erroneous diagnosis. The presence of an USP-6 rearrangement contributes to the diagnosis SVABC; SVABC and most of the previously documented extragnathic GCRGs may be considered within the umbrella of primary aneurysmal bone cysts.
Asunto(s)
Quistes Óseos Aneurismáticos , Diagnóstico Diferencial , Ubiquitina Tiolesterasa/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Quistes Óseos Aneurismáticos/diagnóstico , Quistes Óseos Aneurismáticos/genética , Quistes Óseos Aneurismáticos/patología , Niño , Preescolar , Femenino , Granuloma de Células Gigantes/diagnóstico , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Tumores de Células Gigantes/genética , Neoplasias Maxilomandibulares/genética , Tumores de Células Gigantes/patología , Tumores de Células Gigantes/terapia , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/patología , Granuloma de Células Gigantes/terapia , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Maxilomandibulares/patología , Neoplasias Maxilomandibulares/terapia , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Canales Catiónicos TRPV/genéticaRESUMEN
OBJECTIVES: To investigate the molecular pathogenesis of implant-associated peripheral giant cell granuloma (IA-PGCG). METHODS: A convenience sample of 15 IA-PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho-ERK1/2 was also evaluated by immunohistochemistry. RESULTS: KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild-type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho-ERK1/2 protein in the immunohistochemical analysis. CONCLUSIONS: KRAS mutations and activation of the MAPK-ERK signaling pathway occur in IA-PGCG. This is the first study to demonstrate cancer-associated gene mutations in a non-neoplastic reactive condition associated with dental implants.
Asunto(s)
Implantes Dentales/efectos adversos , Granuloma de Células Gigantes/etiología , Granuloma de Células Gigantes/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Mutación , Transducción de SeñalRESUMEN
The ovulatory LH-surge increases Vegf gene expression in granulosa cells (GCs) undergoing luteinization during ovulation. To understand the factors involved in this increase, we examined the roles of two transcription factors and epigenetic mechanisms in rat GCs. GCs were obtained from rats treated with eCG before, 4 h, 8 h, 12 h and 24 h after hCG injection. Vegf mRNA levels gradually increased after hCG injection and reached a peak at 12 h. To investigate the mechanism by which Vegf is up-regulated after hCG injection, we focused on C/EBPß and HIF1α. Their protein expression levels were increased at 12 h. The binding activity of C/EBPß to the Vegf promoter region increased after hCG injection whereas that of HIF1α did not at this time point. The C/EBPß binding site had transcriptional activities whereas the HIF1α binding sites did not have transcriptional activities under cAMP stimulation. The levels of H3K9me3 and H3K27me3, which are transcriptional repression markers, decreased in the C/EBPß binding region after hCG injection. The chromatin structure of this region becomes looser after hCG injection. These results show that C/EBPß regulates Vegf gene expression with changes in histone modifications and chromatin structure of the promoter region in GCs undergoing luteinization during ovulation.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Regulación de la Expresión Génica , Células de la Granulosa/metabolismo , Luteinización/fisiología , Ovulación/fisiología , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteína beta Potenciadora de Unión a CCAAT/genética , Células Cultivadas , Epigénesis Genética , Femenino , Granuloma de Células Gigantes/genética , Granuloma de Células Gigantes/metabolismo , Granuloma de Células Gigantes/patología , Células de la Granulosa/citología , Código de Histonas , Procesamiento Proteico-Postraduccional , Ratas , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Introducción: La lesión central (LCCG) y periférica (LPCG) de células gigantes de los maxilares, son lesiones reactivas con comportamiento clínico diferente. Objetivo: Comparar la inmunoexpresión de CD68 en células gigantes (CGm) mononucleares (CMn) en lesiones central y periférica de los maxilares. Material y métodos: Se evaluaron 35 casos de LCCG y 24 de LPCG en bloques de parafi na que podían ser procesadas para la expresión del anticuerpo CD68. La inmunoexpresión se valoró en el citoplasma de ambas poblaciones celulares, obteniendo proporciones; la inmunoexpresión se categorizó en intensa, moderada, leve. Las proporciones se compararon con χ2, siendo signifi cativo p ≤ 0.05. Resultados: Para las CGm de LCCG, CD68 se expresó en una proporción de 96 versus 84.2% LPCG (p < 0.005). La proporción de la tinción de la expresión intensa y moderada fue más frecuente en las LCCG (p = 0.032). Las proporciones entre las CMn 59.3% LCCG versus 18.6% en la LPCG (p < 0.001). Hubo diferencia en intensidad de CD68, en las CMn de LCCG fue mayor (p = 0.002). Conclusiones: La alta expresión de CD68 en las CGM y CMn en la lesión central y periférica confi rma su fenotipo de macrófago. Las diferencias entre las proporciones y la tinción a CD68 refl eja mayor actividad fagocítica posiblemente relacionada con el comportamiento clínico (AU)
Introduction: Central (CGCL) and Peripheral (PGCL) giant cell lesions of jaws are reactive lesions displaying diff erent behavior patterns. Objective: To compare CD68 immunoexpression between CGCL and PCGL in giant multinucleated and mononuclear cells. Material and methods: 35 CGCL and 24 PGCL were retrieved from paraffi n-embedded biopsy, as well as the feasibility to analyze CD68 immunoexpression. The immunoexpression was analyzed in cytoplasm both cell populations cellular, for and staining intensity was categorized as intense, moderate or faint. Proportions were compared by χ2, making a p ≤ 0.05 value signifi cate. Results: In 96% of CGCL's in GMCs displayed CD68, as compared to 84.2% in PGCL, (p < 0.005). The proportion of stained cells, intense to moderate staining was more frequent in CGCL (p = 0.032). The proportion CD68 was expressed in 59.3% or CGCL mononuclear cells, as compared to 18.6% in PGCL, (p < 0.001). There was diff erence in staining CD68 intensity between mononuclear cells in CGCL, (p = 0.002). Conclusions: The high CD68 expression frequency in GMCs and mononuclear cells in central and peripheral GCL confi rm a macrophage phenotype; a more intense staining in CGML and GMCs suggests a more active phagocytic activity, and possibility underline the diff erent clinical behavior (AU)
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Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Inmunohistoquímica , Granuloma de Células Gigantes/genética , Enfermedades Maxilomandibulares/inmunología , Antígenos CD , Monocitos/química , Interpretación Estadística de Datos , Distribución por Edad y Sexo , Macrófagos/química , MéxicoRESUMEN
In literature there are few reports about multiple CGCG. But this is the first report of bilateral CGCG of the mandibular angles in three females from the same family.This report describes three cases of females from the same family - a mother and two young daughters - with bilateral CGCG in their jaw angles. All the lesions were surgically removed and the histopathologic diagnosis was always identical: giant cell central granulomas, with patterns that were absolutely superimposable between them and with that of the mother.The hypothesis is that this presentation of CGCG may be defined as hereditary bilateral CGCG of the mandibular angles (or also, cherubism-like lesions).
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Querubismo/genética , Predisposición Genética a la Enfermedad , Granuloma de Células Gigantes/genética , Enfermedades Mandibulares/genética , Monitoreo Fisiológico/métodos , Biopsia con Aguja , Niño , Femenino , Granuloma de Células Gigantes/diagnóstico por imagen , Granuloma de Células Gigantes/patología , Granuloma de Células Gigantes/cirugía , Humanos , Inmunohistoquímica , Enfermedades Mandibulares/diagnóstico por imagen , Enfermedades Mandibulares/patología , Enfermedades Mandibulares/cirugía , Persona de Mediana Edad , Procedimientos Quirúrgicos Orales/métodos , Linaje , Pronóstico , Radiografía Panorámica/métodos , Enfermedades Raras , Medición de RiesgoRESUMEN
Aneurysmal bone cysts (ABCs) mostly occur in the metaphysis of long bones. Primary paranasal ABCs are extremely rare, and most reported cases reveal typical histopathological features including cystic space with fibrous septa and hemorrhage. Solid-variant ABCs or solid ABCs lacking cyst formation may be histologically indistinguishable from giant cell reparative granulomas, giant cell tumor of bone, and brown tumor. Here we report the case of a 24-year-old woman with a paranasal mass diagnosed as USP6-rearranged solid ABC, mimicking giant cell reparative granuloma, giant cell tumor of bone, and brown tumor. For paranasal sinus bone or soft tissue tumors containing numerous giant cells, molecular analysis including the USP6 gene may serve as a useful diagnostic tool to distinguish solid ABCs from other giant cell-rich lesions.
Asunto(s)
Quistes Óseos Aneurismáticos/genética , Reordenamiento Génico , Tumor Óseo de Células Gigantes/genética , Granuloma de Células Gigantes/genética , Enfermedades de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/genética , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genética , Adulto , Quistes Óseos Aneurismáticos/diagnóstico por imagen , Quistes Óseos Aneurismáticos/patología , Quistes Óseos Aneurismáticos/terapia , Diagnóstico Diferencial , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Tumor Óseo de Células Gigantes/patología , Granuloma de Células Gigantes/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Procedimientos Quírurgicos Nasales , Enfermedades de los Senos Paranasales/diagnóstico por imagen , Enfermedades de los Senos Paranasales/patología , Enfermedades de los Senos Paranasales/terapia , Neoplasias de los Senos Paranasales/diagnóstico por imagen , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/terapia , Fenotipo , Valor Predictivo de las Pruebas , Radioterapia Adyuvante , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
INTRODUCTION: We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting. CLINICAL REPORT: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis. There were no haematological cytogenetic anomalies or other haematological pathology to explain the splenomegaly. Metabolic testing and chromosomal microarray were unremarkable. Trio whole-exome sequencing (WES) identified a pathogenic de novo heterozygous germline CBL variant (c.1111T > C, p.Y371H), previously reported to cause CBL syndrome and implicated in development of juvenile myelomonocytic leukemia (JMML). DISCUSSION: CBL syndrome (more formally known as "Noonan-syndrome-like disorder with or without juvenile myelomonocytic leukemia") has overlapping features to Noonan syndrome with significant variability. CBL syndrome and other RASopathy disorders-including Noonan syndrome, neurofibromatosis 1, and Costello syndrome-are important to recognize as these are associated with a cancer-predisposition. CBL syndrome carries a very high risk for JMML, thus accurate diagnosis is of utmost importance. The diagnosis of CBL syndrome in this patient would not have been possible based on clinical features alone. Through WES, a specific genetic diagnosis was made, allowing for an optimized management and surveillance plan, illustrating the power of genomics in clinical practice.
Asunto(s)
Mutación de Línea Germinal , Granuloma de Células Gigantes/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Esplenomegalia/genética , Niño , Granuloma de Células Gigantes/diagnóstico , Humanos , Masculino , Síndrome de Noonan/diagnóstico , Esplenomegalia/diagnósticoRESUMEN
Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas. This report describes the surgical therapy of an NF1-affected female with multilocular mandibular GCG and hypodontia who additionally suffered from a brain tumour and Hashimoto's thyroiditis. Although local recurrence of GCG was noted, augmentation of the curetted cavities with a bone substitute in successive interventions successfully restored the extensive periradicular local defects and stabilised the teeth. A meticulous in vitro study of the GCG specimen revealed a second hit mutation in the NF1 gene in the GCG spindle-cells. This study contributes to the increasing knowledge of the molecular basis for GCG in the jaw of NF1 patients, indicating that it is a neoplasm.