Central giant cell granuloma (CGCG) is a benign aggressive destructive osteolytic lesion of osteoclastic origin1 that ocur in the mandible and maxilla and accounts for approximately 7% of all benign tumours of jaws2. The world health organization (WHO) has defined CGCG as an intraosseous non-neoplastic lesion, consisting of cellular fibrous tissues that contain multiple haemorrhage multinucleated giant cells, and, occasionally trabeculae of woven bone3.
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The nature of CGCG is still controversial. Jaffe was hypothesized that this is a reactive and self curing lesion and included the terminology giant cell reperative granuloma. Later, the neoplastic hypothesis was raised to explain the aggressive subtype4. Recently, both reperative and neoplastic assumptions are true, so that CGCG lesions are patially reactive and partially neoplastic4.
CGCG is an uncommon lesion that occurs in young adults before the age of 30 years with a female preponderance5. There was a peak incidence for males between the age of 10-14 years and for females between 15-19 years of age6. It is more common in the anterior mandible than in the maxilla.
Histological characteristics are highly cellular, fibroblastic stroma with plump, spindle- shaped cells with a high mitotic rate; the vascular density is high. The multinucleated giant cells are prominent throughout the fibroblastic stroma but are not necessarily abundant. They are often located most numerously around of haemorrahge6.
Clinically, CGCG shows a wide variety behavior that is ranging from a non-aggressive, asymptomatic (indolent) and slow growing lesions to an aggressive, large, expansive lesion with rapid growth and aggressive sign and symptoms.
Choung et al.7were the first described between the differences aggressive and non- aggressive lesions based on signs and symptoms and histological features. Aggressive lesions are characterized by one or more of the following features: pain, paresthesia, root resorption, rapid growth, cortical perforation, and a high recurrence rate after surgical curretage.
Radiogically, the lesion appears as a radiolucent area and it can be unilocular or multilocular with either well-defined or can be ill-defined margins8. Multiple lesions are rare and are often associated with a syndrome (i.e. Noonansyndorme, neurofibromatosistype I ) or with cherubism6. The radiological and histological apperances of CGCG are not pathognomatic, and therefore further examination such as blood tests, including calcitonin, phosphate, parathyroid hormone and alkaline phosphate levels must be performed to confirm the diagnosis and to exclude hyperparathyroidism8.
One of the treatment choice for CGCG is curratege with or without adjuvant therapy, i.e. liquid nitrogen, cryosurgery, peripheral ostectomy and Carnoy’s solution and another treatment modality is aggressive en- bloc resection, resulting in varying degrees of deformity5. It results in serious mutilation of the jaw and face. Loss of teeth and of dental germs in young patients is also often unavoidable9. In growing patients, to preserve both aesthetic and functional necessity non-surgical methods such as intralesional injections with corticosteroids, IFN-α 2a and systemic dose of calcitonin are increasingly used by clinicans. These alternative therapeutic strategies come in useful for large aggressive lesions to cure or reduce the size and thus minimize the need for extensive surgical resection that can result in functional and aesthetic deficits in young patients.
Calcitonin therapy for CGCG was first announced by Harris in 1993 and since then several case reports have been published of successful treatment of this lesion using different types of calcitonin and different strategies of administration5.
In this report a patient is presented with massive aggressive CGCG who were treated with salmon calcitonin, as a single treatment modality, after initial treatment with intralesional steroid had failed.
An 8- year- old male patient complaining of a tender/ non-tender swelling on the left mandibular molar area was referred to the oral and maxillofacial surgery service at the Selcuk University, Faculty of Dentistry, in 2010. There was neither medical history nor trauma.
Physical examination …….cm, lymphadenopathy,
Radiographically, in the left mandibular molar area a diffuse radiolucency……
Based on clinical and radiological findings pre-diagnosis of CGCG was made and laboratory investigations were required to eliminate hyperparathyroidism (brown tumors) before treatment. Parathyroid hormone levels were found in normal reference ranges. Additionally low level of haemoglobin and high level of creatinin and phosphate were examined.
An incisional biopsy was performed under local anesthesia. Histologically diagnosis of the lesion was proved as CGCG. Because of the patient’s age and dental development conservative therapy was preferred. Intralesional steroid injections of a solution of Kenacort-A (10 mg/ml triamcinolone aqueous suspension, Bristol-Myers Squibb S.p.A, Loc.ta Fontana del Ceraso, Angani, Italy) were performed during 1 year but there was no resolution in the lesion. After initial steroid treatment was failed authors decided using intranasal (systemic) calcitonin treatment. Miacalcic® 200 IU/day nasal spray (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA) (calcitonin-salmon) was preferred and performed 2 yearlong.
Luckily any side effect was seen and the patient was showed exceptionally good cooperation to treatment and. During systemic calcitonin therapy clinicians must be on the alert about some side effect such as bloating or swelling of the face, arms, hands, lower legs, or feet, chills, cough, difficulty with breathing, difficulty with swallowing, dizziness, fever, itching, joint pain, muscle aches and pains, nausea or vomiting, nervousness, puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue, skin rash, sweating, tightness in the chest, tingling of the hands or feet, trembling or shaking of the legs, arms, hands or feet, trouble sleeping, unusual weight gain or loss.
Following calcitonin therapy there was a decrease in tumor size that was observed clinically. Preserving the teeth and growing jaw bone for natural mastication and facial aesthetic the tumor was not decided to operate. The patient has a three- year follow up and has any clinical or radiological sign or symptoms.
CGCG is an uncommon lesion that occurs more frequently in females. In most cases it appears before the age of 30 years. Mandibular lesion is more often than the maxillary lesion with a ratio 2:1. In the mandible the anterior and posterior regions are equally affected while in the maxilla, the anterior region is usually affected.???(ant. Mu post. Mu)
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The clinical behavior of CGCG ranges from a slow growing asymptomatic swelling to an aggressive lesion that presents pain, local bone destruction, root resorption or tooth displacement. Some authors have classified CGCG into two types, based on clinical and radiographic features. The first is non-aggressive CGCG, which is characterized by slow, almost asymptomatic growth that does not perforate the cortical bone or induce root resorption and has a low tendency to recur. The second is aggressive CGCG, which is characterized by pain, rapid growth, expansion, and perforation of the cortical bone, radicular resorption and high tendency to recur.
Histologically, CGCG is characterized by the presence of multinucleated giant cells (MGC) in background composed of mononucleated stromal cells (MSC) with ovoid or spindle-shaped mesenchymal nuclei. The giant cells are typically seen in a hemorrhagic field containing numerous poorly defined vascular channels, which may be quite prominent. A patchy distribution of cellular elements is one feature that helps differentiate CGCG fromtrue giant cell tumors. In aggressive lesions, Ficarra et al. reported more numerous giant cells in CGCG and Nougeria et al. showed that in aggressive lesions MGCs are usually more numerous, larger and uniformly scattered throughout the lesion.
Flanagan et al. were the first to demonstrate that giant cells in CGCGs are osteoclasts through osteoclast- specific monoclonal antibodies staining. This report was provide in vitro reaction of giant cells to calcitonin and showed the behavior of giant cells in cortical bone excavation typical of osteoclasts. It has been demonstrated that giant cells express calcitonin receptors. Calcitonin therapy is based on these findings. It is though those giant cells are directly inhibited in their function by calcitonin.
Others, however, debate that CGCGs develop from mononuclear precursor cells and, as such, are part of the granulocyte/macrophage lineage or are primarily of fibrotic origin.
Although giant cells are the most prominent histopathological feature of CGCGs, the focus of interest has shifted to the role of the mononuclear cells. Recent studies have shown that mononuclear cells, rather than the giant cells are proliferating compartment responsible for the biological activity of the lesion. de Lange et al. reported that the giant cells of CGCG are derived from subset of mononuclear phagocytes. These mononuclear precursor cells differentiate into mature giant- cells under the influence of RANKL expressing, proliferating, spindle shaped (osteoblastlike) stromal cells.
Nougeria et al. designed a study to determine receptors of MGCs and find out their origin. This study showed, positive immunohistochemical expression of receptor activator of nuclear factor –kB (RANK), tartrate- resistant acid phosphatase (TRAP), vitronectin receptor (VNR) and calcitonin receptor and these findings have suggested on osteoclastic phenotype for MGCs. The presence of CD68 glycoprotein and alpha-1-antichymotrypsin has suggested that MGCs have a macrophage/hystiocyte origin.
In the light of these findings aim of the treatment of CGCGs should include both inhibit osteoclastic activity of the lesion and inhibit the differentiation of macrophage/ hystiocyte precursors into osteoblast like cells. Traditional treatment for CGCGs is surgical curettage. Some authors proposed excision via curettage for treatment of CGCGs and the overall recurrence rate has been reported to range from 16 % to 49 %. A higher incidence of recurrence was found in aggressive CGCG and younger patients, especially males. In growing patients, aggressive surgical approaches may result in facial deformities and patients may lose some of tooth germs. Eisenbud et al. indicate that surgical curettage with peripheral osteotomy is still not the safest treatment for CGCGs especially in aggressive lesions.
The functional and aesthetic alterations as well as the psychological consequences caused by the surgical treatment of CGCG have encouraged researchers to look for effective alternative therapeutic strategies. Alternative therapeutic options for CGCGs are systemic calcitonin intralesional injection of corticosteroids and IFN-α.
Calcitonin has been administered as a nosespray and as subcutaneous daily injections. Recently only nosespray form is available. This hormone increases the influx of calcium into the bones, functions as an antagonist to parathyroid hormone, and inhibits osteoclastic bone resorption. Calcitonin has also been hypothesized to directly inhibit giant cells. In 1993 Harris was first reported total remission of CGCGs in 4 patients. On the contrary Kaban et al (1999) observed a significant growth following calcitonin therapy.
Response of patients to calcitonin therapy is variable. Many factors can contribute to the various responses to calcitonin which have been reported in the literature. The different types of calcitonin (human, salmon) and the different types of administration (subcutaneous injections, nasal spray) are some of these factors.
With regard to the efficacy of calcitonin therapy, 3 phenomena have been recognized:
- Primary resistance or primary non-response is noted.
- There is the so-called plateau phenomenon, denoting that the alkaline phosphates serum levels cannot be lowered beyond a certain point, irrespective of the calcitonin dose.
- The third potential problem is secondary resistance, also called the escape phenomenon. Patients who initially react well to calcitonin show a diminished reaction after some time. Increased activity of osteoclasts through loss of calcitonin receptors is the more likely explanation for this phenomenon.
Intralesional corticosteroids injection for CGCGs treatment was first reported by Jacoway et al. (1988). This method hypothesized that the extracellular production of bone- resorption- mediating lysosomal proteases by giant cells in inhibited by steroids which also induce apoptosis of the osteoclast- like cells. In English literature, complete remission results from intralesional administration of corticosteroids in insufficient and the number of patients is very small. Especially, in large cases intralesional corticosteroid therapy may not be effective and may not provide of reduction in size. No reports in which the effectiveness of intralesional corticosteroid injection for CGCG is described separately for the aggressive type and non- aggressive type are available.
Nougeria et al. indicated that MGCs may be similar to osteoclasts and macrophages/hystiocytes and that CGCG can be prompted to respond to calcitonin or intralesional glucocorticoid as shown in the literature. They reported the expression of glucocorticoid and calcitonin receptors in CGCG before and after treatment with intralesional injection of steroids. They concluded that glucocorticoid receptor expression in the MGCs was higher in patients with a good response. The difference in calcitonin reseptor expression was not statistically significant between the aggressive and non- aggressive lesions and between the patients with a good response and with a modatare/negative response to treatment. Although aggressive CGCG had higher calcitonin receptor expression no significant difference in calcitonin receptor expression in different clinical forms of CGCG was found in this study. The treatment response was determined using previously described scores. In which four criteria were considered: stabilization or regression of the lesion size evaluated clinically and in follow-up radiographs; the absence of sumptoms; increased radio-opacity in radiographs, representing peripheral and/or central calcification of the lesion, increased difficulty in solution infiltrating the lesion during the sequence of applications. If a case provided all of these, the response was determined to be good; providing two or three criteria was determined to be moderate; and providing one criteria or no criteria implied a negative response to treatment.
Another alternative therapeutic agent is IFN-α, it has angiogenic potential and it is a mediator in differentiation from mesenchymall cells to osteoblasts thus leading to an increase in bone apposition. Similar to corticosteroids IFN-α is also capable of stopping rapid growth of their lesions and reducing their size, but it still necessary to use additional surgery to eliminate the lesion. In the literature only one case report was showed complete remission with IFN-α therapy. Several reports suggest that IFN-α administered as a monotherapy for aggressive CGCGs is useful for inhibiting the rapid growth of lesions and for reducing their size. Total remission of lesion cannot be achieved, because IFN-α has no direct inhibiting effect on proliferating tumor cells and additional surgery is probably still required to eliminate lesions. Therefore, the effectiveness of monotherapy with IFN-α is still questionable.
CGCG is found predominantly in young adults. Surgical treatment of these patients might have resulted in physical and psychological disorders, such as developmental disorder of the mandible, dysfunction of mastication, and facial deformities, non- surgical treatment with systemic calcitonin administration which is a minimally invasive procedure and less costly and should be considered the first choice for treatment of CGCG in young patients.
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