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-related antigen and muscle cell actin. Six cases of PGCG were also studied by transmission electron microscopy. RESULTS: Vimentin, alpha I-antichymotrypsin and CD68 were expressed in both the mononuclear and multinucleated giant cells. Dendritic mononuclear cells, positive for S-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 multinucleated 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: Immunohistochemical 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.

Total Spontaneous Regression of a Central Giant Cell Granuloma After Incisional Biopsy: A Four-Year Follow-Up Case Report

Central giant cell granuloma (CGCG) of the jaws represents a localized and benign neoplastic lesion sometimes characterized by aggressive osteolytic proliferation. The World Health Organization defines it as an intraosseous lesion composed of cellular and dense connective tissues that contain multiple hemorrhagic foci, an aggregation of multinucleated giant cells, and occasional bone tissue trabeculae. The origin of this lesion is uncertain; however, factors such as local trauma, inflammation, intraosseous hemorrhage, and genetic abnormalities have been identified as possible causes. CGCG generally affects those younger than 30 years and occurs more frequently in women (2: 1). This lesion corresponds to approximately 7% of all benign tumors of the jaws, with prevalence in the anterior region of the jaw. Aggressive lesions are characterized by symptoms, such as pain, numbness, rapid growth, cortical perforation, root resorption, and a high recurrence rate after curettage. In contrast, nonaggressive CGCGs have a slow rate of growth, may contain sparse trabeculation, and are less likely to move teeth or cause root resorption or cortical perforation. Nonaggressive CGCGs are generally asymptomatic lesions and thus are frequently found on routine dental radiographs. Radiographically, the 2 forms of CGCG present as radiolucent, expansive, unilocular or multilocular masses with well-defined margins. The histopathology of CGCG is characterized by multinucleated giant cells, surrounded by round, oval, and spindle-shaped mononuclear cells, scattered in dense connective tissue with hemorrhagic and abundant vascularization foci. The final diagnosis is determined by histopathologic analysis of the biopsy specimen. The preferred treatment for CGCG consists of excisional biopsy, curettage with a safety margin, and partial or total resection of the affected bone. Conservative treatments include local injections of steroids, calcitonin, and antiangiogenic therapy. Drug treatment using antibiotics, painkillers, and corticosteroids and clinical and radiographic monitoring are necessary for approximately 10 days after surgery. There are only a few cases of spontaneous CGCG regression described in the literature; therefore, a detailed case report of CGCG regression in a 12-yearold boy with a 4-year follow-up is presented and compared with previous studies. (c) 2014 American Association of Oral and Maxillofacial Surgeons

Central Giant Cell Granuloma in Pediatric Maxilla: Surgical Management

Central giant cell granuloma (CGCG) is an intraosseous lesion consisting of fibrous cellular tissue that contains multiple foci of hemorrhage, multinucleated giant cells, and occasional trabeculae of woven bone. An 8-year-old boy presented himself complaining of a painless swelling in the left maxilla that had started 1 year. Computed tomography (CT) scan confirmed a poorly defined multilocular radiolucent lesion in the left maxilla crossing the midline. The patient underwent enucleation through an intraoral approach of the lesion. The biopsy revealed multinucleated giant cells in a fibrous stroma. A CT was taken approximately 1 year postoperatively. There was no clinical or radiographic evidence of recurrence. Therefore, surgical treatment of CGCG can be performed, trying to preserve the surrounding anatomic structures, which can be maintained in case the lesion does not show an aggressive clinical behavior, avoiding large surgical defects which are undesirable in children.

Central giant cell granuloma

Background: Central giant cell granuloma is a benign condition of the jaws which may present an aggressive behavior. Case report: A 9-year-old boy was complaining of swelling in the floor of the mouth. A solid swelling was observed in the area of the lower incisors. From the radiographic exam, we observed a radiolucent image in the mandibular bone with well-defined limits extending from the apical region of tooth 33 to the apical region of tooth 42. Discussion: Due to the diagnosis and the age of the patient, we chose a conservative treatment, administering subcutaneous injections of calcitonin. During this treatment, no reduction to the lesion was observed. Therefore, we chose to treat the lesion with triamcinolone acetonide. Monthly follow-ups demonstrated good lesion reduction and the absence of any clinical symptoms during the first 2 years. After a 3-year follow-up, the patient returned, presenting mobility of the lower incisors. A significant increase in the size of the lesion was observed. After a biopsy, with the removal of tissuewhich had the appearance of a cyst capsule, microscopic analyses were found to be compatible with a secondarily infected cyst. Two months following this procedure, the patient did not present tooth mobility anymore and the oral mucosa presented a normal aspect. Following a radiographic exam, full lesion repair was observed. These conservative treatments should be the first option in cases of central giant cell granuloma and the patient must be observed for a long period of time, until no further clinical or radiographic signs of lesions are observed

Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics

Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n 5 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

Treatment of central giant cell lesions using bisphosphonates with intralesional corticosteroid injections

Central giant cell lesions are benign intraosseous proliferative lesions that have considerable local aggressiveness. Nonsurgical treatment methods, such as intralesional corticosteroid injections, systemic calcitonin and interferon have been reported. Recently, bisphosphonates have been used to treat central giant cell lesions. A case of a 36-year-old male with a central giant cell lesion crossing the mandibular midline was treated with intralesional corticosteroids combined with alendronate sodium for the control of systemic bone resorption. The steroid injections and the use of bisphosphonates were stopped after seven months when further needle penetration into the lesion was not possible due to new bone formation. After two years, the bony architecture was near normal, and only minimal radiolucency was present around the root apices of the involved teeth. The patient was followed up for four years, and panoramic radiography showed areas of new bone formation. Thus far, neither recurrence nor side effects of the medication have been detected.

Giant cell bone lesions in the craniofacial region: a diagnostic and therapeutic challenge

Background: Giant cell tumors of bone (GCTs) are common in the long bones, but rare in the craniofacial region, with only 1% of cases occurring in the latter. Clinical, radiological, and anatomical diagnosis of this locally aggressive disease, which occurs in response to trauma or neoplastic transformation, poses a major challenge in clinical practice. Methods: The present study describes a series of 4 cases and highlights the main features of the differential diagnosis and treatment of these lesions: GCT, giant cell reparative granuloma (GCRG), and the brown tumor of hyperparathyroidism. Results: GCT presents as a benign neoplasm, most typically affecting the knees, and rarely in the temporal and sphenoid bones. It is radiologically indistinguishable from GCRG due to its lytic, poorly defined appearance. The distinction can only be made microscopically, as the presence of multinucleated giant cells scattered throughout the stroma and the absence of a history of trauma favor a diagnosis of GCT. The brown tumor of hyperparathyroidism occurs with rapid, localized osteoclast activity secondary to the effects of increased parathyroid hormone (PTH) levels; parathyroid examination is indispensable. Conclusion: The diagnosis and treatment of these lesions poses a major challenge due to their similar clinical presentation and radiological appearance. Accurate diagnosis is essential for definition of appropriate management, as complete resection is the goal in GCT and GCRG to avoid recurrence, whereas the brown tumor often yields to treatment of the underlying hyperparathyroidism.

Intralesional corticosteroid injections in the treatment of central giant cell lesions of the jaws

Objective: The aim of this study was to evaluate the response of treatment of central giant cell lesion to intralesional corticosteroid injections. Study Design: Review of articles indexed in PubMed on the topic between the years 1988 and 2011, and development of a descriptive meta-analysis of the results. Results: Sample of 41 patients primarily treated with intralesional corticosteroid injections was obtained, with a male female ratio of 1:0.95, being 23 aggressive and 18 non-aggressive central giant cell lesions. Triamcinolone acetonide and triamcinolone hexacetonide were the drugs used, and 78.0% cases were considered as good result, 14.6% were considered as moderate response and 7.3% were considered as negative result to treatment. Considering the aggressiveness, 88.9% of non-aggressive lesions presented a good response to treatment, in aggressive central giant cell lesions, 69.6% presented a good response to intralesional corticosteroid injections. Conclusion: In view of the results analyzed, intralesional corticosteroid injections could be considered as first treatment option for central giant cell lesion.

Utility of temporal artery biopsy samples for genome-wide analysis of giant cell arteritis

Giant Cell Arteritis (GCA) is the most common vasculitis affecting the elderly. Archived formalin-fixed paraffin-embedded (FFPE) temporal artery biopsy (TAB) specimens potentially represent a valuable resource for large-scale genetic analysis of this disease. FFPE TAB samples were obtained from 12 patients with GCA. Extracted TAB DNA was assessed by real time PCR before restoration using the Illumina HD FFPE Restore Kit. Paired FFPE-blood samples were genotyped on the Illumina OmniExpress FFPE microarray. The FFPE samples that passed stringent quality control measures had a mean genotyping success of >97%. When compared with their matching peripheral blood DNA, the mean discordant heterozygote and homozygote single nucleotide polymorphisms calls were 0.0028 and 0.0003, respectively, which is within the accepted tolerance of reproducibility. This work demonstrates that it is possible to successfully obtain high-quality microarray-based genotypes FFPE TAB samples and that this data is similar to that obtained from peripheral blood.

Suspected giant cell arteritis:A study of referrals for temporal artery biopsy

Background: The purpose of this study is to describe the nature of cases undergoing temporal artery biopsy (TAB) for suspected giant cell arteritis (GCA). Methods: A retrospective review of case notes was undertaken for all patients on whom ophthalmologists had performed TAB in 2 teaching hospitals between 1995 and 2001. Presenting symptoms, referring specialty, TAB result, treatment, and discharge diagnosis were recorded. Results: Ophthalmologists performed TAB on 110 patients for suspected GCA. A variety of specialties referred patients to ophthalmology for TAB; presenting symptoms varied with referral source. Of the 110 TABs, 21 (19%) were reported as positive for GCA, 84 (76%) were negative, and 5 (4.5%) were reported as inadequate. The symptoms most commonly associated with a positive TAB were visual disturbance (15/21) and headache (15/21).The odds ratios for having a positive TAB result rather than a negative result were 1.0 for the presence of headache, 4.1 for visual disturbance, and 6.7 for jaw claudication. Interpretation: Physicians were faced with a different population of GCA suspects than ophthalmologists. While physicians should be alert to the significance of visual symptoms or jaw claudication, ophthalmologists should be ready to facilitate prompt TABs when appropriate. TAB should be performed promptly and an adequate length of artery taken for biopsy. An argument can be made that TAB is not needed in cases of suspected GCA. However, a positive result provides firm justification for the use of steroids. We feel that TAB has a useful role and we make reference to methods to maximize its usefulness.

Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

Acute Upper Limb Ischemia, a Rare Presentation of Giant Cell Arteritis

Giant cell arteritis (GCA) is a systemic large vessel vasculitis, with extracranial arterial involvement described in 10-15% of cases, usually affecting the aorta and its branches. Patients with GCA are more likely to develop aortic aneurysms, but these are rarely present at the time of the diagnosis. We report the case of an 80-year-old Caucasian woman, who reported proximal muscle pain in the arms with morning stiffness of the shoulders for eight months. In the previous two months, she had developed worsening bilateral arm claudication, severe pain, cold extremities and digital necrosis. She had no palpable radial pulses and no measurable blood pressure. The patient had normochromic anemia, erythrocyte sedimentation rate of 120 mm/h, and a negative infectious and autoimmune workup. Computed tomography angiography revealed concentric wall thickening of the aorta extending to the aortic arch branches, particularly the subclavian and axillary arteries, which were severely stenotic, with areas of bilateral occlusion and an aneurysm of the ascending aorta (47 mm). Despite corticosteroid therapy there was progression to acute critical ischemia. She accordingly underwent surgical revascularization using a bilateral carotid-humeral bypass. After surgery, corticosteroid therapy was maintained and at six-month follow-up she was clinically stable with reduced inflammatory markers. GCA, usually a chronic benign vasculitis, presented exceptionally in this case as acute critical upper limb ischemia, resulting from a massive inflammatory process of the subclavian and axillary arteries, treated with salvage surgical revascularization.

Granulocyte macrophage colony-stimulating factor enhances the modulatory effect of cytokines on monocyte-derived multinucleated giant cell formation and fungicidal activity against Paracoccidioides brasiliensis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Differentially expressed genes in giant cell tumor of bone

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)