Evaluation of p53, PCNA, Ki-67, MDM2 and AgNOR in oral peripheral and central giant cell lesions

OBJECTIVES: Peripheral giant cell lesion (PGCL) and central giant cell lesion (CGCL) of the jaws have a distinct clinical behaviour. Whether such biological differences are supported by a distinct pattern of proliferation markers or cell cycle associated proteins expression is not known. Therefore the purpose of the present study was to compare the immunohistochemical expression of p53, MDM2, Ki-67, PCNA and the histochemical expression of argyrophilic nuclear organiser region (AgNOR) on PGCL and CGCL of the jaws. MATERIALS AND METHODS: Paraffin wax blocks of 14 cases of PGCL and 12 cases of CGCL were retrieved. A biotin-streptavidin amplified system was used for identification of the antigens. The AgNOR number was also evaluated. RESULTS: Ki-67 immunoreactivity was greater in the mononuclear cells of PGCL compared to CGCL. PCNA and AgNOR staining were similar in PGCL and CGCL. Prominent MDM2 immunoreactivity was observed in all tissues investigated. By contrast, there was no p53 immunoreactivity. CONCLUSIONS: Although CGCL present a more aggressive clinical behaviour, it has a decreased proliferative activity compared to PGCL. Finally, p53, MDM2, PCNA, Ki-67 immunohistochemical expression and AgNOR histochemical expression do not reflect their distinct biological behaviour.     

PCNA and Ki-67 immunoreactivity in multinucleated cells of giant cell fibroma and peripheral giant cell granuloma

Immunohistochemical investigation of PCNA and Ki-67, two diverse nuclear proteins essential to the cell cycle, was undertaken in archival, formalin-fixed and paraffin-embedded specimens of giant cell fibroma (GCF) and peripheral giant cell granuloma (PGCG). GCF multinucleated cell nuclei were mostly PCNA⁺, although there was variability in staining intensity. This indicates heterogeneity in nuclear PCNA metabolism of GCF multinucleated cells, and it is possible that the most intensely stained nuclei have passed through the cell cycle more recently compared to the less immunoreactive nuclei. However, the absence of Ki-67 immunoreactivity in GCF multinucleated cells, and absence of mitoses in GCF multinucleated cells, suggests that cell cycling in the absence of cytokinesis is not involved in GCF multinucleated cell formation. Alternatively, GCF multinucleated cells possibly form by fusion of mononuclear cells previously identified as fibroblasts, although this theory cannot be confirmed by the data presented in this study, and the histogenesis of GCF multinucleated cells remains unclear. In contrast, absence of either PCNA or Ki-67 immunoreactivity in PGCG multinucleated cells is consistent with an osteoclast lineage and formation from differentiated mononuclear cells.     

Stromal myofibroblasts in central giant cell granuloma of the jaws cannot distinguish between non-aggressive and aggressive lesions

OBJECTIVE: To investigate correlations between myofibroblast density (MFD) and biological behavior of a large series of non-aggressive and aggressive central giant cell granuloma lesions (CGCGs). METHODS: Twenty-four non-aggressive and 17 aggressive lesions were immunohistochemically stained with alpha smooth muscle actin. MFD was assessed using the point counting method in the lesions' core tissue and in control areas that consisted of non-involved, connective tissue surrounding the lesion. RESULTS: All CGCGs contained myofibroblasts among the stromal cells. No significant differences were found in the mean percentage of MFD (%MFD) of non-aggressive (20.8 +/- 15.7%) and aggressive (23.7 +/- 22.9%) lesions (P > 0.05) or in the mean %MFD of the respective control areas (1.4 +/- 2.2% and 1.7 +/- 4.1%; P > 0.05). The mean core tissue %MFD of both lesion types was significantly higher than that of the control areas (P < 0.001). CONCLUSION: Myofibroblasts were an integral component of CGCG stromal cells, but their density could not distinguish between non-aggressive and aggressive lesions.     

Cellular mechanisms of osteoclast formation and lacunar resorption in giant cell granuloma of the jaw

BACKGROUND: Giant cell granuloma (GCG) is an osteolytic tumour of the jaw which is characterised by the presence of both mononuclear and multinucleated (osteoclast-like) giant cell components. The nature of these component cells and the pathogenesis of the extensive osteolysis associated with this lesion is uncertain. METHODS: Using cell culture techniques and immunohistochemistry, we defined the phenotypic characteristics of the mononuclear and multinucleated cells present in four cases of GCG of the jaw. We also analysed the cellular and humoral factors associated with osteoclast formation and osteolysis in these tumours and determined whether GCG stromal cells are capable of supporting osteoclast formation. RESULTS: GCG-derived giant cells expressed the phenotypic characteristics of osteoclasts (TRAP+, VNR+, and calcitonin responsive) and were capable of lacunar resorption. In addition to macrophages, the mononuclear cell population contained numerous spindle-shaped stromal cells which proliferated in culture and expressed RANKL; these GCG-stromal cells were capable of supporting human osteoclast formation from circulating monocyte precursors. CONCLUSION: Our findings indicate that the giant cells in GCG of the jaw are osteoclast-like and formed from monocyte/macrophage precursors which differentiate into osteoclasts under the influence of RANKL-expressing mononuclear stromal cells found in this lesion.     

Periapical central giant cell granuloma misdiagnosed as odontogenic cyst

AIM: To present the clinicopathological features of a series of four periapically located central giant cell granulomas (CGCGs) that were misdiagnosed and treated as being of endodontic origin. SUMMARY: Four cases of periapical CGCGs were submitted with a clinical diagnosis of either radicular or residual cyst. In two cases, root canal treatment had been performed previously. The patients were two women and two men whose age ranged from 31 to 85 years. Two cases were located in the mandibular premolar-molar region, and two in the anterolateral region of the maxilla. Two lesions were submitted for histological examination with a diagnosis of radicular cyst whereas the remaining two were submitted with a diagnosis of residual cyst. KEY LEARNING POINTS: Periapical giant cell lesions may be unilocular and therefore misdiagnosed as an endodontic lesion because of their radiographic similarity to an inflammatory periradicular lesion, especially if the teeth have been root filled or if the vitality is negative or doubtful. It is important to follow up the healing process of a periapical radiolucency related to a root filled tooth and, in case of persistence, to perform surgery and to submit the specimen for histological examination.     

A recurrent central giant cell granuloma in a young patient and orthodontic treatment: a case report

Central giant cell granuloma (CGCG) is an uncommon benign intraosseous lesion of the jaw, found predominantly in children and young adults below 30 years of age. The purpose of this article was to present a summary of the current literature and a case report of an 11-year-old boy diagnosed with an aggressive CGCG involving the anterior maxilla that was removed in 2004 and subsequently recurred almost 3 years later in 2006. The presenting features of the patient and the effect of combined surgical and orthodontic treatment for this condition are discussed. This case shows how the dentition was successfully maintained with conservative surgery and orthodontic treatment in spite of the extensive destruction of the supporting bone, and the importance of long-term follow-up. The report also reminds orthodontic practitioners that rare pathological conditions can occur in their child patient groups.     

Intravascular fibrin thrombi and endothelial cell damage in central giant cell granuloma

Two cases of central giant cell granuloma were studied ultrastructurally. The majority of vessels showed intravascular fibrin thrombi and endothelial cell damage, with gaps in their walls. Plasma, red cells and fibrin were seen subendothelially. The basal lamina was absent from endothelial cells where these components were in contact with their plasma membrane; otherwise it showed multiplication. It is suggested that the absence of basal lamina is the result of degeneration and that these vessels are probably venules and capillaries rather than lymphatics. Myofibroblasts were the dominant stromal cells. Giant cells had little phagocytic activity. It seems that the main function for the stromal cells is the repair of the haematoma and the damaged vessels. It is proposed that the term giant cell reparative granuloma is appropriate, but it should not be used indiscriminately for all jaw lesions containing giant cells.     

Unusual aggressive behavior of central giant cell granuloma following tooth extraction

Central giant cell granuloma (CGCG) is found exclusively in jaws. Its etiopathogenesis is unclear; however it is suggested that it can arise as a reactive response to trauma. This report describes an aggressive variety of CGCG which raises a question; can extraction of tooth modify the behavior of CGCG? A 46 years old male had reported with a rapidly increasing intraoral and extraoral swelling of lower jaw following tooth extraction. Radiographic examination revealed a large multilocular lesion involving the body and ramus of mandible which had been proved to be aggressive CGCG on histopathological examination. The importance of radiographic examination prior to extraction of teeth and importance of inclusion of CGCG in jaw swellings associated with mobility of teeth or failure of healing sockets is emphasized.     

Peripheral giant cell granuloma. An immunohistochemical and ultrastructural study

OBJECTIVE: To study the nature of multinucleated and mononuclear cells from peripheral giant cell granuloma (PGCG).
MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded sections of 40 cases of PGCG were immunohistochemically stained for vimentin, alpha I-antichymotrypsin, CD68, S-100 protein, lysozyme. leucocyte common antigen (LCA), factor VIII-retated antigen and muscle cell actin. Six cases of PGCG were also studied by transmission etectron microscopy.
RESULTS: Vimentin, alpha I-antichymotrypsin and CD68 were expressed in both the mononuclear and multinucleated giant cells. Dendritic mononuclear cells, positive for 5–100 protein, were noted in 67.5% of the lesions, whereas lysozyme and leucocyte common antigen were detected in occasional mononuclear cells. Ultrastructural examination showed mononuclear cells with signs of phagocytosis and sometimes interdigitations with similar cells. Others presented non-specific characteristics and the third type exhibited cytoplasmic processes and occasional Birbeck granules. Some multi-nucleated giant cells showed oval nuclei, abundant mitochondria and granular endoplasmic reticulum whereas others presented with irregular nuclei and a great number of cytoplasmic vacuoles.
CONCLUSIONS: lmmunohistochemical and ultrastructural results suggest that PGCGs of the jaws are composed mainly of cells of the mononuclear phagocyte system and that Langerhans cells are present in two thirds of the lesions.     

Neurofibromatosis type 1 associated with bilateral central giant cell granuloma of the mandible

Neurofibromatosis type 1, or von Recklinghausen disease, is one of the most common hereditary neurocutaneous disorders in humans. Clinically, Neurofibromatosis type 1 is characterized by café-au-lait spots, freckling, skin neurofibroma, plexiform neurofibroma, bony defects, Lisch nodules and tumors of the central nervous system. Central giant cell granuloma is a benign central lesion of bone, primarily involving the jaws, of variably aggressive nature characterized by aggregates of multinucleated giant cells in a background of cellular vascular fibrous connective tissue and spindle-shaped mononuclear stromal cells. The association between neurofibromatosis and central giant cell granuloma has been reported in the literature. A case of mandibular bilateral central giant cell granuloma in a patient with Neurofibromatosis type 1 was conservatively but successfully treated by adequate surgical curettage of mandibular bone lesions.     

SH3BP2-encoding exons involved in cherubism are not associated with central giant cell granuloma

Central giant cell granuloma (CGCG) is a benign lesion with unpredictable biological behaviour ranging from a slow-growing asymptomatic swelling to an aggressive lesion associated with pain, bone and root resorption and also tooth displacement. The aetiology of the disease is unclear with controversies in the literature on whether it is mainly of reactional, inflammatory, infectious, neoplasic or genetic origin. To test the hypothesis that mutations in the SH3BP2 gene, as the principal cause of cherubism, are also responsible for, or at least associated with, giant cell lesions, 30 patients with CGCG were recruited for this study and subjected to analysis of germ line and/or somatic alterations. In the blood samples of nine patients, one codon alteration in exon 4 was found, but this alteration did not lead to changes at the amino acid level. In conclusion, if a primary genetic defect is the cause for CGCG it is either located in SH3BP2 gene exons not yet related to cherubism or in a different gene.     

颌骨巨细胞瘤和巨细胞肉芽肿病变中多核巨细胞性质的探讨

目的 探讨颌骨巨细胞瘤(Giant cell tumor，GCT)和巨细胞肉芽肿(Giant cell granuloma，GCG)病变中多核巨细胞(Multinucleated giant cells，MGCs)的性质及组织来源。方法 对8例颌骨GET和8例GCG(中心性4例、外周性4例)进行酶组织化学和免疫组织化学观察，并与其它含MGICs的口腔病变(如异物反应、淋巴结结核等)进行比较。结果 颌骨GCT和GCG中的MGCs既可表达组织细胞／单核巨噬细胞相关抗原[如CD68、αl-抗胰蛋白酶(Alpha-1-antitrypsin，AAT)、α1-抗糜蛋白酶(Alpha-1-antichymotrypsin，AACT)、溶菌酶等]，又具有破骨细胞特异性酶-抗酒石酸酸性磷酸酶[Tartrate-resistant acid phosphatase(TRAP)]的活性，但不表达增殖细胞标记Ki-67抗原。结论 颌骨GCT和GCG中的MGCs可能是反应性终末分化细胞，由病变中处于不同分化阶段的前体破骨细胞融合而成．同时具有单核巨噬细胞和破骨细胞的某些表型特征。     

Comparison of giant cell granuloma of the jaw and non-ossifying fibroma

The present investigation concerns 113 patients with peripheral giant cell granulomas, 52 patients with central giant cell granulomas and 18 patients with non-ossifying fibromas of the long bones. The purpose was to analyze the possible equivalence of central giant cell granulomas with non-ossifying fibromas. Non-ossifying fibromas occur at a lower mean age than central giant cell granulomas and moreover, although central giant cell granulomas may exhibit areas that are histologically similar to non-ossifying fibromas, the presence of other features, especially bone formation, warrants a recognition of central giant cell granulomas and non-ossifying fibromas as separate entities.     

A comparative immunohistochemical evaluation of CD68 and TRAP protein expression in central and peripheral giant cell granulomas of the jaws

J Oral Pathol Med (2011) 40 : 334–337 Background: Giant cell granulomas of the jaws are lesions that arise either peripherally in periodontal ligament and mucoperiosteum or centrally in the bone. The aim of this study was to evaluate expression of CD68 and tartrate‐resistant acid phosphatase (TRAP) proteins in multinucleated giant cells and mononuclear cells. Methods: Formalin‐fixed and paraffin‐embedded tissue section of 20 specimens of central giant cell granuloma and 20 cases of peripheral giant cell granuloma were immunohistochemically analyzed for CD68 and TRAP proteins expression rate using Biotin‐Streptavidin method. Result: In central giant cell granuloma, more than 99% of multinucleated giant cells were positive for TRAP antibody and about 90% were positive for CD68. In mononuclear cells of this lesion, 14% of cases were positive with TRAP antibody and 8% with CD68. In peripheral giant cell granuloma, TRAP antibody was positive in 99% of giant cells and in 13% of mononuclear cells. A proportion of 97% of giant cells and 6% of mononuclear cells reacted positively with CD68. Conclusion: Immunohistochemical evidence of this study shows that giant cells and a group of mononuclear cells of stroma in both peripheral and central giant cell granuloma express TRAP antibody severely that is specific for osteoclast. Also, these cells are positive reactive to CD68, which is the macrophage marker and therefore it can be mentioned that giant cells are osteoclast, although their origins are macrophagic/monocytic or their precursors, and maybe mononuclear cells in stroma have a role in formation of giant cells.     

Human cytomegalovirus in peripheral giant cell granuloma

Background:  The peripheral giant cell granuloma is a relatively common non-neoplastic inflammatory lesion of gingiva, but the etiopathogeny remains unknown. This study aimed to evaluate the importance of human cytomegalovirus and Epstein–Barr virus in a peripheral giant cell granuloma of a 47-year-old female.
Methods:  The lesion was studied clinically, histopathologically, immunologically and virologically using established procedures.
Results:  The gingival growth was located at the mesial surface of the maxillary left canine having a vital pulp. The mass was 12 × 21 mm in size and exhibited a smooth surface with no evidence of fluctuation on palpation. An excisional biopsy revealed giant cells in a fibrohistiocytic stroma with areas of haemorrhage. Serum protein levels and lymphocyte subsets were within normal limits, except CD3⁺ and CD4⁺ cells were below normal ranges. Polymorphonuclear leukocytes expressed p150,95 (CD11c/CD18) and CXCR-2 receptors within normal ranges, but the CXCR1 receptor showed decreased density, and CD15 were below normal range. A virological sample of the tooth surface adjacent to the gingival swelling yielded 7.6 × 10³ copy-counts of cytomegalovirus and 4.3 × 10³ copy-counts of Epstein–Barr virus.
Conclusions:  The clinical and histological findings were consistent with the diagnosis of peripheral giant cell granuloma. Cytomegalovirus has the potential to induce multinucleated giant cells, and the possibility that the virus contribute to the development of peripheral giant cell granuloma merits further study.     

Central giant cell granuloma of the jaws: assessment of cell cycle proteins

BACKGROUND: Several reports have demonstrated the presence of a high proliferative activity in central giant cell granuloma, raising the possibility that deregulation of the cell cycle may contribute to its pathogenesis. As we identified alterations of cyclin D1 in giant cell tumor of bone, and as there are histologic similarities between central giant cell granuloma and giant cell tumor, we assessed jaw lesions for the presence of similar alterations. METHODS: Formalin-fixed, paraffin-embedded tissue from 29 cases of central giant cell granuloma was assessed for the expression of cyclin D1, cyclin B1, and MIB-1 (Ki-67) using immunohistochemistry. In addition, differential polymerase chain reaction (PCR) was used to determine whether there was cyclin D1 gene amplification. RESULTS: The cyclin D1 gene copy number appeared to be minimally elevated in 31% of the cases. Cyclin D1 protein overexpression was observed in 28 of 29 cases (96.5%). Immunostaining was present predominantly in the nuclei of the giant cells. Cyclin B1 and MIB-1 immunoreactivity was restricted to the mononuclear cells with no staining present in the giant cells. CONCLUSIONS: Cyclin D1 protein overexpression may be involved in the formation of the giant cells and the pathogenesis of central giant cell granuloma. As the distribution of immunostaining is identical to that observed in giant cell tumor of bone, our results support the possibility that central giant cell granuloma of the jaws and giant cell tumor of bone represent a similar disease process that clinically and histologically may have somewhat different features because of differences in the anatomical site of involvement.