|Year : 2014 | Volume
| Issue : 1 | Page : 47-53
Central giant cell granuloma of the jaws and giant cell tumor of long bones: A clinicopathological, cytometric and immunohistochemical comparative study
Manal A Al Sheddi1, Hezekiah A Mosadomi2, FH Al Dayel3
1 Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, Riyadh, Saudi Arabia
2 Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Riyadh Colleges of Dentistry and Pharmacy, Riyadh, Saudi Arabia
3 Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
|Date of Web Publication||2-Jan-2014|
Manal A Al Sheddi
Department of Oral Medicine and Diagnostic Sciences, King Saud University, Riyadh
Source of Support: This study was supported by grant no. Frameworks
-8-15 of KACST, Riyadh, KSA, Conflict of Interest: None
Aim: Central giant cell granuloma (CGCG) of the jaws and giant cell tumor (GCT) of bone share a number of similarities and dissimilarities in respect of their histopathological, cytometric and immunohistochemical features. The aim of this study was to compare CGCG of the jaws and GCT of long bones from clinicopathology, cytometry and immunohistochemistry aspects.
Materials and Methods: 18 CGCG and 22 GCT of bones were compared. Clinical data were obtained on the age, gender, diagnosis, clinical course, treatment and follow up. Histopatholgical features of mononuclear cell; stroma and giant cells were assessed. Computer-assisted image analysis was used to measure the mean number of giant cells, mean number of nuclei per giant cell, fractional surface area and relative size index. Expression of cell differentiation markers (vimentin, CD68, CD34, S-100P, alpha-smooth muscle actin [αSMA]) and cell cycle related markers (PCNA, P53, Ki-67, bcl-2) were evaluated.
Results: CGCG of the jaw showed an early age of presentation (55.6% <25 years) and the mandible was the more common anatomical location (77.8), whereas the femur and tibia were equally affected by GCT (36.4%). GCT showed higher mean number of giant cells, higher number of nuclei per giant cell, greater fractional surface area and relative size index. Both diseases showed similar cellular phenotype in respect of Vimentin, S100 protein, CD68 and CD34. There was increased immunoreactivity of GCT to Ki-67, P53 and αSMA.
Conclusion: The findings suggested that the GCT and the CGCG may be variants of the same disease entity with age and site-specific features.
Keywords: Central giant cell granuloma, cytometry, giant cell tumor, immunohistochemistry
|How to cite this article:|
Al Sheddi MA, Mosadomi HA, Al Dayel F H. Central giant cell granuloma of the jaws and giant cell tumor of long bones: A clinicopathological, cytometric and immunohistochemical comparative study. Saudi J Oral Sci 2014;1:47-53
|How to cite this URL:|
Al Sheddi MA, Mosadomi HA, Al Dayel F H. Central giant cell granuloma of the jaws and giant cell tumor of long bones: A clinicopathological, cytometric and immunohistochemical comparative study. Saudi J Oral Sci [serial online] 2014 [cited 2019 Nov 19];1:47-53. Available from: http://www.saudijos.org/text.asp?2014/1/1/47/124190
| Introduction|| |
Central giant cell granuloma (CGCG) of the jaw is a lesion characterized histologically by multinucleated giant cells in a background of ovoid to spindle-shaped mesenchymal cells.  It occurs most commonly in the anterior part of the mandible of young patients and has a predilection for females.  Radiogaphically, CGCG presents as a unilocular or a multilocular radiolucent lesion with a variable clinical behavior and unpredictable course.  Some lesions show slow growth and do not recur, whereas others exhibit rapid growth, cortex perforation and a tendency to recur after excision. ,
Giant cell tumor (GCT) of bone, on the other hand, is a relatively common neoplasm, accounting for 21% of all benign primary tumors of bone.  It is a locally aggressive neoplasm located near the articular end of tubular bones , (The typical radiographic appearance of a GCT is entirely lytic and expansile lesion in the epiphysis, usually without peripheral bone sclerosis or periosteal reaction.  Histologically, the tumor consists of a moderately vascularized network of stromal cells and multinucleated giant cells meagerly interspersed with collagenous fibrils. The stromal cells are mononuclear and in general resemble young connective tissue cells. They are spindle shaped or ovoid in varying proportions. 
The prognosis of GCT is unpredictable. Up to 50% of the lesions recur if treated by curettage alone and rare cases of metastasis have been reported. , Although the CGCG and GCT are regarded as distinct clinical entities, yet they are difficult to differentiate histologically and the pathologist cannot predict their clinical behavior or prognosis with a great deal of confidence. , considered CGCG as a reactive lesion and GCT as a neoplastic lesion, whereas some authors consider CGCG and GCT as variants of the same disease. ,
The existence of a "true" GCT of the jaws is uncertain, , although few cases of what was considered to be GCT of the jaws have been described in the literature. , On the basis of controversy and debatable criteria that surround the relationship between CGCG of the jaws and GCT of the long bones as reported in the literature since 1940, this study aimed to compare CGCG of the jaws and GCT of long bones from clinicopathology, cytometry and immunohistochemistry aspects.
| Materials and Methods|| |
Paraffin wax blocks of 40 cases (22 GCT, 18 CGCG) were retrieved from the histopathology archives of three centers: King Faisal Specialist Hospital and Research Center, College of Dentistry, King Saud University and Riyadh Medical Complex, all in Riyadh, Saudi Arabia. Clinical data were obtained from the records of the patients in respect of age, sex, diagnosis, location, clinical course, laboratory investigations including histopathology, treatment and follow-up. New sections were made from paraffin-embedded specimens, stained with hematoxylin and eosin and reviewed to confirm the diagnosis.
The available microscopic slides on each case were reviewed and the histologic features of the mononuclear cells, stroma and giant cells were assessed. Each feature listed in [Table 1] was graded on 0 to 3+ scale. The predominant shapes of mononuclear cells (ovoid, spindle, or mixture of two) were evaluated categorically as predominantly spindle, predominantly ovoid, or mixed. All fields on the slides were examined as they would be routinely examined in a histopathology laboratory setting. Multiple sections were viewed when available. Although histologic features sometimes varied from field to field, the overall and predominant histologic appearance was the focus of histologic profiling.
Immunohistochemical studies were performed on 4-μm-thick, formalin-fixed, paraffin-embedded sections using immunohistochemical markers listed in [Table 1].
A refined avidin-biotin technique was used.  To determine tumor mononuclear cell profile, the number of cells positive for CD68, alpha-smooth muscle actin (αSMA), Ki67, Vimentin, S100p, PCNA, P53 and bcl2 were counted in four fields (250x) and expressed as percentages to the total cell count in each field. Tumor giant cell were excluded in the counts. For CD34, staining was quantitated as percentage of positively stained area to the measurement field and presented as area percentage.
For each case, giant cells in 4 randomly selected fields were measured with the use of Leica image processing and analysis system (Leica - Cambridge) at standard frame setting at magnification 250x . The parameters assessed were the mean number of giant cells, the mean number of nuclei per giant cell, the fractional surface area (%) occupied by the giant cells per unit area in 4 fields and the relative size index of the giant cells, which was calculated as the fractional surface area divided by the number of giant cells in the field.
A non-parametric analysis (Mann-Whitney test) was used to compare both groups of CGCG and GCT. The values were considered significantly different when the P < 0.05. The correlation between the diagnosis and the clinical parameters were assessed by Chi-square test.
| Results|| |
The ages of CGCG patients ranged from 7 to 64 years at the time of diagnosis with a mean of 35.5 years. More than half of the cases (55.6%) were under 25 years of age at the time of initial diagnosis. There was a distinct gender predilection of 72.2% females to 27.8% males. The mandible was involved in fourteen cases (77.8%), the maxilla in three cases (16.7%). Four cases (22.2%) showed anterior mandible location, five cases (27.8%) were confined to posterior mandible and five cases (27.8%) involved the anterior and posterior mandible. Radiographs were available for thirteen cases. Radiographic findings ranged from incidental radiolucencies on routine radiographic examination to large destructive multilocular radiolucency that involved adjacent bones. Six cases (46.2%) were multilocular in appearance, with some exhibiting honeycombed pattern. Seven cases (53.9%) were unilocular. Seven cases (53.9%) had displaced roots and six cases (46.2%) showed evidence of root resorption. Data on recurrence was available for ten of the eighteen cases. An overall recurrence rate of 40% was found in the ten cases reviewed. Three cases out of four were females under 17 years of age. One case were a 7 years old male. Follow-up information was available for nine patients. The mean follow-up time was at 36 months with a range from 1 to 9 years.
The age range of GCT was 19-49 year at the time of initial diagnosis, with a mean of 34 years. Eleven cases (50%) were between 26 and 38 years of age, seven cases (31%) were above 39 years of age and four cases (18.2%) were under 25 years of age. Female to male ratio was 2.1:1. The femur and tibia were equally affected by the lesion, each accounting for 36.4%. All femoral lesions affected the distal part, whereas proximal tibia was involved in six of the eight tibial cases. The radius was involved in three patients (13.6%). Radiographs were available for 18 cases. All the lesions were osteolytic. Radiographic findings were unilocularity and multilocularity destructive appearances. Soft-tissue involvement was noted in 10 cases. Sclerosis at the margins was noted in three cases. Recurrence developed in ten cases that were followed-up for at least 2 years. Out of the ten patients, 8 patients had recurrences within 1 year following initial treatment, one after 2 years and one patient after 4 years. Follow up was extended to a period of 2-13 years with a mean follow up period of 7.5 years.
Various histologic features and patterns were seen in both groups of giant cell lesions. Common to all lesions included in this study, was the presence of multinucleated giant cells in a stroma composed of ovoid-shaped and/or spindle-shaped mesenchymal cells. There were no statistically significant differences between CGCG of jaws and GCT of bones in all histological features tested with the exception of necrosis for which GCTs showed higher scores.
Cytometric parameters measured are summarized in [Table 2]. There was a statistically significant difference in each of all the parameters measured between the two groups. The mean number of giant cell per four high power fields, the mean number of nuclei per giant cell, the fractional surface area and the relative size index were significantly greater in GCT compared with CGCG.
[Figure 1] shows the mean percentage of positive cells per total number of cells in 4 high power fields for CGCG and GCT for the nine markers used. There was increased immunoreactivity of GCT to Ki-67 (P = 0.003), p53 (P < 0.001) and αSMA (P = 0.05) [Figure 2], [Figure 3], [Figure 4].
|Figure 1: Immunohistochemical staining results (% of positive cells/total number of cells in 4 high power fields, Where are your negative controls (IgG 1 and IgG 2a) in this figure). SMA: Smooth muscle actin, VIM: Vimentin|
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|Figure 2: Expression of alpha smooth muscle actin in central giant cell granuloma (a) and giant cell tumor (GCT). (b) Most mononuclear cells in GCT were positive (×200)|
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|Figure 3: Ki-67 expression in central giant cell granuloma (a) and giant cell tumor (b) (×200)|
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|Figure 4: P53 expression in central giant cell granuloma (a) and giant cell tumor. (b) Some giant cells in both lesions show nuclear immunoreactivity to p53 (×200)|
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| Discussion|| |
One of the major difficulties in a retrospective study of this type is the unavoidable lack of standardization in fixation and processing of biopsy materials particularly when multiple centers are involved. Nevertheless, even with these limitations the results for cases within the same category were fairly consistent. Immunohistochemical staining for each marker was applied to all the 40 cases at the same time and under the same staining conditions in an attempt to reduce variable staining expressions that may be explainable by inconsistent staining procedures. One observer read all the data and 20% of the readings were repeated. Repeated intra-observer reliability was high (>86%).
CGCG of jaws showed an early age of presentation (55.6% were under 25 years of age) compared with GCT of bone in which 50% were between 26 and 38 years of age. These findings are in agreement with previous studies in which up to 75% of CGCG cases appeared before age of 30 years. ,, All the GCT cases were above 19 years of age with a peak incidence in the third decade of life, which is in agreement with previous studies  . A female predominance (72.2% of CGCG, 68.2% GCT) found in the present study is also in agreement with other studies. ,,, Previous studies ,, have shown that the mandible, especially the anterior region, is the most common location for CGCGs. In the present study, mandibular involvement is in agreement with those previous reports as 77.8% of the cases were in the mandible.
Previous studies ,, have shown that the mandible, especially the anterior region, is the most common location for CGCGs. In the present study, mandibular involvement is in agreement with those previous reports as 77.8% of the cases were in the mandible.
Anterior mandible involvement represented 22.2% of the cases compared with 27.8% were in posterior mandible and 27.8% were in posterior and anterior mandible. The apparently lower percentage of anterior mandible involvement in this study compared with other studies does not preclude that anterior mandible is involved by the lesion more than any other location considering the lesions extending from anterior to the posterior region.
Most GCTs are found near the end of major tubular bone of extremities , ). Femur and tibia were equally affected by the lesion (36.4%), followed by radius (13.6%). Distal femur and proximal tibia were the most common locations. The anatomical locations of GCTs in the present study are in agreement with previous reports in which the majority of the lesions occurred around the knee joint, most commonly in the distal femur  and the proximal part of the tibia. 
Although 53.8% of the CGCGs of the jaws were unilocular, a significant number (46.2%) were multilocular. This finding is in disagreement with Whitaker and Waldron  who reported that a majority of the lesions (61%) were multilocular, whereas 39% of the lesions were unilocular. Root resorption was evident in 46.2% of the cases. This percentage of root resorption is in agreement with Whitaker and Waldron  but is relatively greater than indicated in an earlier report.  Giant cell ganulomas are generally very vascular lesions,  and on angiograms might mimic vascular tumors, so it is important to arrive at a diagnosis based on clinical, radiographical and histological examinations prior to treatment planning. The high vascularity seen in the angiograms of two cases of giant cell granulomas led to clinical diagnosis of vascular tumors. Recurrence and follow-up data were not available for all the 18 CGCGs cases studied. An overall recurrence rate of 40% was found in the cases reviewed of which three out of four were females and under 17 years of age. One case was a 7-year-old male. The mean follow-up time was 36 months. Previous studies have reported recurrence rates that varied between 11% and 35% respectively. , The mean reported interval between diagnosis and initial treatment and treatment of recurrence was 21 months and very few recurrences manifested after 2 years of initial treatment. ,, GCT recurred in 45.5% of the cases, which had been followed-up for at least 2 years. The majority of the recurrences occurred within 1 year of initial treatment. This rate of recurrence is in agreement with previous studies. , Long-term follow-up is essential in assessing the results of therapy for GCT, because malignant change has been known to occur as late as 40 years after primary treatment. When a GCT recurs, it usually occurs within the first 2 years after treatment. However, recurrences may be seen as late as 7 years. 
Some histological differences reported to be more common in CGCG when compared to GCT included the presence of large areas of fibrosis, hemorrhage, hemosiderin deposits and osteoid. ,, Due to the considerable overlap of these features, these differences have not proved to be diagnostically reliable. 
In the present study, we evaluated these histological parameters quantitatively and there were no differences between the two lesions. Necrosis, which was prominent in GCTs in our series, is a common finding in GCTs and some tumors are almost completely necrotic. 
Dahlin  attempted to establish the histopathologic criteria for the diagnosis of a "true" GCT microscopically. However, there is still confusion as to what constitutes a "true" GCT.
Lesions that bear giant cells, such as giant cell granuloma, osteosarcoma and some other lesions must be considered in the differential diagnosis. 
Several previous studies that compared GCTs of long bones with giant cell lesions of the jaws have clearly shown that a subset of jaw lesions clearly fall within histological profile accepted for GCTs and conversely some long bone lesions show the histological features widely accepted for giant cell granulomas. ,
The cytometric measurements employed in the current study, included mean number of giant cells per four high power fields, mean number of nuclei per giant cell, fractional surface area and relative size index were found to be significantly greater in GCT than in CGCG of the jaws. A study by Franklin et al.  used a stereological technique to compare histological parameters of the giant cell component in 10 CGCG of the jaws and 10 GCT of long bones. There was a significant difference between the two lesions in respect of both nuclear numerical density and mean absolute cell volume. In their attempt to determine the absolute value for giant cell volume they utilized certain mathematical assumptions about the shape of giant cells. They found out that the mean absolute values for cell volume in giant cells of long bone lesion were significantly smaller than those in CGCG of jaws. Nuclear density was higher in GCT.
In the current study, they only markers showing significant difference were p53, Ki67 and SMA. Immunophenotyping studies have compared the expression of S-100 protein, human leukocyte antigen-D-related and CD68 antigens in CGCG and GCT, with inconclusive results. , Expression of cell cycle regulatory proteins has been used to distinguish neoplastic from reactive conditions and to predict their biological behavior in malignant tumors. p53, MDM2, Ki-67 and PCNA proteins are examples of oncogenes, tumor suppressor genes and proliferation markers widely studied in the literature in many tumors and reactive conditions. , CGCG has a higher proliferative activity than GCT. Furthermore, it was suggested that p53 inactivation by MDM2 expression may be involved in the pathogenesis of giant cell lesions of the jaws and long bones.  Reactivity to SMA is a possible indicator of myofibroblastic differentiation.  El-Labban and Lee  suggested that myofibroblasts form the major part of stromal cells in CGCG based on ultrastructural study. On the other hand, immunoreactivity for SMA in GCT of the bone is an issue of controversy. , Although actin expression in the fibroblast-like tumor cells of GCT can be explained by the electron microscopic observation that these tumor cells occasionally contain abundant microfilaments in their cytoplasm, , its significance is unclear. Myofibroblastic differentiation of these tumor cells is unlikely because of their electron microscopic features. Their lack of the dense patch, basal lamina and fibronexus seems to be considerably different from myofibroblasts, except the existence of their filaments. 
CD34 positive cells were restricted to tumor-supporting capillaries. It is apparent from this and other studies that the origin of the mononuclear cells in CGCGs is not the endothelial cell. , The vascular density of giant cell lesions of the jaws reported to be significantly increased in aggressive lesions, but failed to act as a predictor of the GCT behavior. ,,
| Conclusion|| |
The findings indicated that some CGCG of the jaws and GCT of the extragnathic skeleton may not be distinct and separate entities but rather represent a continuum of a single disease process modified by age of the patient, location and possibly other factors that are yet not clearly understood.
| Acknowledgment|| |
This study was supported by grant no. Frameworks -8-15 of KACST, Riyadh, KSA.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]