Central giant cell granuloma of the mandible in a 7-year-old boy: A case report

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Central giant cell granuloma (CGCG) is a rel- atively uncommon benign bony lesion of a variably aggressive nature, accounting for less than 7% of all benign jaw lesions.1 The condition was first identified in 1953 by Jaffe,2 who initially termed this lesion a central giant cell reparative granuloma. Nowadays, as a reparative response is quite rare and most lesions of CGCG are destructive, the word reparative has been deleted from that term.3,4 In contrast to the giant cell tumors of the long

bone, CGCG of the jaw tends to involve a younger age group, and, though categorized as “aggressive,” CGCG is much less destruc- tive than giant cell tumors, which are usually painful and fast growing, with a pathologic fracture being the first sign in about 10% of cases.5

Auclair et al6 performed a histomorpho- logic comparison of 49 CGCGs of the jaw and 42 giant cell tumors of long bones; the only statistically significant histologic differ- ence between these 2 lesions was the high- er number of nuclei in the giant cell tumors.

Al Sheddi et al7performed a similar compar- ison between 18 CGCGs of the jaw and 22 giant cell tumors of bone. A result similar to Auclair et al’s report6 was obtained, but, in addition, necrosis was a significant finding in lesions of CGCG. Wold et al8also compared the CGCGs of the small bones of the hands and feet with giant cell tumors of the same bones. They reported 100% osteoid forma- tion, 93% stromal hemorrhage, 73% cluster- ing of giant cells, and a 20% stromal stori- form pattern in their 30 cases of CGCG lesions, whereas all these were lacking in giant cell tumors of the same bones, except for hemorrhage in 44%.

Central giant cell granuloma of the mandible in a 7-year-old boy: A case report

Yu-Ju Lin, DDS1/Hong-San Chen, DDS, PhD2/

Hong-Rong Chen, DDS, PhD3/Wen-Chen Wang, DDS, MS4/ Yuk-Kwan Chen, DDS, MS5/Li-Min Lin, DDS, MS, PhD6

Central giant cell granuloma is a relatively uncommon benign bony lesion of a variably aggressive nature. This paper presents the case of a 7-year-old boy with central giant cell granuloma in the anterior mandible. In children with mixed dentition, a pathologic lesion could be the underlying cause of regular tooth mobility and exfoliation of primary teeth and can easily be overlooked, especially in cases that are not accompanied by an obvious bony expansion. The clinician needs to be aware of possible oral pathology when tooth mobility and displacement are present, and central giant cell granuloma should be consid- ered in the differential diagnosis for children with maligned and mobile teeth.

(Quintessence Int 2007;38:253–259)

Key words: central giant cell granuloma, child, differential diagnosis, tooth exfoliation

1Chief Resident, Department of Oral Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.

2Associate Professor and Head, Department of Pediatric Dentistry, Kaohsiung Medical University, Kaohsiung, Taiwan.

3Professor, Department of Oral and Maxillofacial Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.

4Attending staff, Department of Oral Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.

5Assistant Professor and Head, Department of Oral Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.

6Professor, Department of Oral Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.

Reprint requests: Dr Yuk-Kwan Chen/Dr Li-Min Lin, Department of Oral Pathology, School of Dentistry, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan.

E-mail: k0285@ms22.hinet.net

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Furthermore, in contrast to the giant cell tumors of the long bone, in which en bloc excision is the treatment of choice, curettage is usually the first line of treatment and is fre- quently adequate for CGCG of the jaw. Small fragments that may be left behind do not necessarily require further treatment, and sometimes appear to resolve spontaneously.

A minority of these tumors is more aggres- sive, and recurrence follows incomplete removal; frequently, however, a second curet- tage appears to be adequate. Wide excision is only occasionally required for otherwise uncontrollable lesions.9Therefore, the failure to distinguish between CGCG of the jaw and giant cell tumors prior to 1953, resulted, according to Jaffe, in overtreatment of many young patients.2

The origin of CGCG is unknown, but some indications implicate genetic abnor- mality. Two small genetic studies on lesions of CGCG have been reported.10,11 Cytoge- netic abnormalities involving translocations between sex chromosomes and autosomes were identified in a case of CGCG of the pha- lanx.10Also, by using DNA microarray, sever- al genes covering a wide range of functional activities, including cell cycle regulation, sig- nal transduction, and vesicular transport, have been discovered to be up- or downreg-

ulated in 2 surgically resected CGCGs of the mandible; some genetic markers have been identified that can potentially assist in identi- fying the biologic behavior (such as quies- cent versus aggressive) or that are potential disease-specific targets for therapy.11 Additional cases of CGCG must therefore be studied to determine the specificity and sig- nificance of these findings.10,11

On the other hand, cyclin D1 protein over- expression has been found to be involved in the formation of the giant cells of CGCG of the jaw; hence, deregulation of the cell cycle may contribute to the pathogenesis of CGCG.12 The light microscopic, enzymatic, histochemical, immunochemical, and ultra- structural features of these giant cells are similar to those of normal osteoclasts.12 Furthermore, there has been experimental evidence to indicate that the multinucleated giant cells of CGCG are formed by the fusion of the mononuclear stromal cells, endothelial cells of capillaries, fibroblasts, myofibrob- lasts, or osteoclast progenitor cells.13 How- ever, a more recent study has claimed that although the multinucleated giant cells of CGCG share some similarities with the osteo- clasts, they demonstrate phenotypic differ- ences from each other, suggesting a distinct precursor.14

Lesions* Traditional diagnostic tools Molecular approach

Brown tumor of Radiographic finding: Loss of lamina dura NA hyperparathyroidism of teeth, multiple lytic radiolucencies

Blood chemistry: Elevated parathyroid hormone secretion, hypercalcemia, hypophosphatemia

Cherubism Radiographic finding: Multiple lytic Mutation in SH3BP2 on p-arm of

radiolucencies chromosome 4

Neurofibromatosis type 1 Radiographic finding: Multiple lytic Mutation in a NF-1 gene on q-arm of

(NF1) radiolucencies chromosome 17

Noonan syndrome Radiographic finding: Multiple lytic Mutation in PTPN11 on q-arm of

radiolucencies chromosome 12

(NA) Not yet clinically available.

*Histologically and radiographically, all of these lesions are essentially indistinguishable.

A clinical-radiological-molecular approach is required to obtain a final diagnosis.

Primary occurrence is due to hyperplasia or neoplasia of the parathyroid gland;

secondary occurrence is associated with renal osteodystrophy.

Ta b l e 1 Differential diagnosis of lesions with histology indistinguishable from central giant cell granuloma in the jaw15–18

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Importantly, a number of lesions are histo- logically indistinguishable from CGCG of the jaw, including brown tumor of primary or secondary hyperparathyroidism,15 cheru- bism,16 and a number of other inherited syn- dromes, such as neurofibromatosis type 117 and Noonan syndrome.18 The differential diagnosis using traditional diagnostic tools together with a molecular approach is sum- marized in Table 1.15–18

In a review of English-language medical lit- erature, most cases of CGCG were reported to appear between the ages of 10 and 30 years.1,3,4,19–22 Well-documented cases of CGCG in children under 10 years old without association with an inherited syndrome have seldom been reported.23–26Furthermore, while CGCG is generally an asymptomatic lesion, enlarged cases have been known to cause tooth mobility or tooth displacement.1,3,4,19–22

Such symptoms and signs may easily be over- looked as regular tooth exfoliation of primary teeth in children with mixed dentition.

This report presents an interesting case of a 7-year-old boy who initially presented with the symptoms and signs of tooth mobility and was ultimately diagnosed with CGCG.

CASE REPORT

A 7-year-old Chinese boy presented with a 4- month history of a painless swelling over the anterior mandibular area. According to his mother, the mandibular right primary central incisor had exfoliated itself, and no swelling of the mandibular right anterior area was noted. Subsequently, the mandibular left pri- mary lateral incisor had severe mobility and was pulled out by the patient. Mobility of the mandibular left primary central incisor was then evident. The patient was taken to a near- by local dental clinic for examination. It was assumed that the tooth mobility was caused by the underlying undererupted permanent counterparts, and consequently the clinician extracted the mandibular left primary central incisor without conducting a radiographic examination. The swelling continued to enlarge, however, and permanent teeth had not yet erupted.

The patient’s family history was unremark- able. His medical history revealed a trauma about 1 year previously consisting of a knock against the anterior mandibular area, accom- panied by a laceration to the chin requiring stitches. Extraoral examination revealed a healthy boy with a mild facial asymmetry in the chin area. The swollen area was hard in consistency, without overlying hyperemia.

The patient did not have any symptoms or signs of infection. Intraoral examination revealed a 3 ⫻ 2-cm firm swelling in the mandibular anterior region, with a smooth, bluish surface (Fig 1). There was no associ- ated tenderness, and the patient did not have any motor or sensory disturbance. Routine laboratory tests revealed that blood chem- istry data were within normal limits.

Panoramic radiography revealed a well- defined monolocular radiolucency over the anterior mandibular area, with a maximum diameter of about 3 cm, extending between the mesial aspects of the mandibular right permanent central incisor and the mandibu- lar left primary canine, as well as from the alveolar crest down to about 2 cm above the inferior cortex of the mandible. Displacement of the mandibular left permanent central and lateral incisors was noted, but no root resorp- tion was observed in the affected teeth.

Furthermore, the mandibular left primary canine had been pushed downward to the inferior border of the mandible (Fig 2).

Mandibular occlusal radiography revealed lingual expansion of the cortical bone (Fig 3).

The patient was subsequently referred to the Department of Oral and Maxillofacial Surgery for an incisional biopsy under local anesthesia, and the specimen was submitted to the Department of Oral Pathology for histopathologic examination. Microscopic examination revealed cellular vascular con- nective tissue with a proliferation of osteoclast- type giant cells with multiple nuclei.

Granulation tissue rich in mononuclear inflam- matory cells and hemosiderin pigments was also observed, consistent with CGCG (Fig 4).

The patient subsequently underwent curettage of the mass under general anes- thesia. The wound was closed with inter- rupted sutures to prevent hematoma forma- tion. The patient tolerated the procedure

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well. The postoperative course was uncom- plicated, and the patient was discharged on postoperative day 3.

The histologic findings of the surgical specimen were similar to the previous inci-

sional biopsy, and a diagnosis of CGCG was again rendered. No recurrence was noted 6 months postoperatively. Unfortunately, we are unable to report beyond 6 months because contact with the patient has been lost.

Fig 1 A swelling with a smooth, bluish surface in the mandibular ante- rior region.

Fig 2 Panoramic radiography reveals a well-defined monolocular radiolucency over the anterior mandibular area, extending between the mesial aspects of the right permanent central incisor and the left primary canine and from the alveolar crest down to about 2 cm above the infe- rior cortex of the mandible. Displacement of mandibular left permanent central and lateral incisors is noted.

Fig 3 Mandibular occlusal radiography reveals lingual expansion of the cortical bone.

Fig 4 Histologic examination reveals a cellular vascular connective tissue with a proliferation of osteoclast-type multinucleated giant cells and granulation tissue rich in mononuclear inflammatory cells and hemosiderin pigments (hematoxylin-eosin stain; original magnification ⫻ 40).

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DISCUSSION

CGCG primarily occurs in the jaw and facial bones, but it is also found in other areas of the body.1 It is usually an asymptomatic lesion discovered during routine radiographic exam- inations, or when the painless expansion of the affected bone is noted by the patient or the parents, as in the present case.1,3,4CGCG lesions usually grow slowly; however, as in the present case, they occasionally present with a relatively high growth rate.20

Usually, as in this case, lesions of CGCG are painless and do not induce paresthe- sia.1,20,27 However, it has been reported that 5% to 11% of these lesions are painful.4,19,20 Although CGCG can be seen in every age group, it occurs more frequently in patients under the age of 30.1,3,4,19–22To the best of our knowledge, there have been only 4 well-doc- umented cases of CGCG in patients under 10 years old without association with an inherited syndrome.23–26 In children with mixed dentition, a pathologic lesion may be the underlying cause of regular tooth mobility and exfoliation of primary teeth and can easi- ly be overlooked, especially in cases that are not accompanied by an obvious bony expan- sion. The clinician needs to be aware of any possible oral pathology when tooth mobility and displacement are present. In these cir- cumstances, radiographic examination is of the utmost importance. As evidenced by this case, the possibility of CGCG should be con- sidered in the differential diagnosis for chil- dren with maligned and mobile teeth.

While previous studies reported CGCG to predominantly affect females, with occur- rence between 56% and 64%,21,28–31the pres- ent case describes CGCG in a young boy.

However, our case is consistent with previous reports of CGCG presenting in the mandible more often than the maxilla and tending to occur in the anterior region of the molars and across the midline (although a recent review of 80 CGCG cases reported an equal predilection for the posterior mandible29).

Local trauma and intraosseous bleeding have been regarded as possible causes of CGCG lesions; however, a history of trauma before the development of the lesion was

determined in only 1 of 32 CGCG cases in the report of Andersen et al.21In the current case, a traumatic event prior to the occur- rence of the lesion could be identified. Other hypotheses of the development of CGCG include its association with other preexisting bony lesions, such as fibrous dysplasia, it being of neoplastic nature or representing an idiopathic reactive process.32The etiology of CGCG is therefore not well understood but, as mentioned above, genetic mutation is claimed to be involved.10,11

The radiographic appearance of CGCG is not pathognomonic.3,20 Both unilocular and multilocular lesions are possible, but multi- locular lesions show a slight predominance over the unilocular lesions.4,20Interestingly, a statistically significant correlation between the locularity of lesions and their size has been suggested, with small lesions usually appearing as unilocular radiolucent and large lesions usually appearing as multilocu- lar.1,20The present case is consistent with this assumption.

Some reports have divided the lesions of CGCG into 2 categories4,28,33,34: (1) Non- aggressive lesions exhibit a slow growth rate, do not exhibit root perforation in teeth affect- ed by the lesion or cortical perforation, and often show new bone formation; (2) aggres- sive lesions grow quickly and are associated with pain, cortical perforation, and root resorption. The present case, as demon- strated clinically and radiographically, sug- gested a nonaggressive lesion. The develop- ment of any additional swelling within 4 months of curettage should be a clinical alert for the risk of recurrence. The incidence of recurrence of a nonaggressive lesion is between 4% and 20%, whereas a local aggressive lesion has a higher recurrence rate.1,28

As stated in Table 1, histologically, a num- ber of systemic or genetic conditions can present with lesions that are indistinguish- able from CGCG lesions of the jaw.

Therefore, differential diagnosis based on a clinical-radiological-biochemical-molecular approach is required to obtain a final diagno- sis. This case, however, revealed no associa- tion with systemic and genetic diseases.

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Simultaneous occurrence of CGCG with other lesions, such as odontogenic kerato- cyst35and central odontogenic fibroma,36has also been reported. Hybrid CGCG and cen- tral odontogenic fibroma of the jaw have been associated with an increased risk of recur- rence following curettage.36It is recommend- ed that a careful search for a possible lesion coexisting with CGCG always be performed.

Surgical curettage is usually employed for smaller lesions of CGCG of the jaws, as per- formed in our case. For aggressive lesions, en bloc surgical resection is occasionally used.9 Recently, weekly intralesional corti- costeroid injections,37,38 daily subcutaneous administration of calcitonin,39and the use of interferon alpha40have also been suggested as possible treatments for large or multiple lesions to avoid the need for mutilating sur- gery in growing children. The main draw- back to these nonsurgical approaches is the need for continual treatment over a pro- longed time period. Radiation treatment is contraindicated because of the potential for malignant transformation.37–39

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