Aggressive giant cell lesion of mandible–confusing to common: true neoplasm versus reactive lesion

  1. Santha Devy Arumugam 1,
  2. Bharathraj Kanniyappan 2,
  3. Umamaheswari Giri 1 and
  4. Sivaramakrishnan Muthanandam 1
  1. 1 Oral & Maxillofacial Pathology and Oral Microbiology, Sri Balaji Vidyapeeth University, Pondicherry, India
  2. 2 Oral & Maxillofacial Surgery, Sri Balaji Vidyapeeth University, Pondicherry, Puducherry, India
  1. Correspondence to Dr Santha Devy Arumugam; drsantha73@gmail.com

Publication history

Accepted:07 Apr 2023
First published:04 May 2023
Online issue publication:04 May 2023

Case reports

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Abstract

Destructive lesions in the craniofacial region especially in the jawbones, if associated with giant cells, include a spectrum of lesions that pose difficulty in diagnosis. The nature of such a lesion in the jawbones is questionable about whether it is a reactive/benign lesion or aggressive/non-aggressive. Clinical, radiological and histopathological correlation may be a reliable indicator to differentiate between the qualities of the lesion, which directly accounts for effective and individual planning of the treatment. Here we present a case of a woman in her late 20s with an unusual destructive lesion of the mandible.

Background

Giant cells are unique large cells that usually contain single or multiple nuclei seen either in physiological or pathological conditions.1 There are many different types of giant cells, which occur under different conditions and assume different configurations.2 3 Multinucleated giant cells (MGCs) are polykaryons usually formed by the fusion of several individual cells derived from multiple lineages, and the most accepted concept was that they arise from the fusion of non-replicating monocytes.2 4 5 They are more commonly associated with granulomatous inflammation as a consequence of infection or reaction to exogenous substances such as keratin, fat and cholesterol crystals, and also appear in autoimmune, neoplastic and genetic disorders.3 5 However, in these conditions, giant cells are not a component of primary pathology, rather they are part of an immunological process that regulates inflammation, infection and neoplasia.3 MGCs are also usually encountered in much of oral and maxillofacial pathology. Mohajerani et al, in their epidemiological study in the Iran population, reported that 6.36% of oral biopsies in their laboratory were containing MGC lesions and they also concluded that such lesions were common in female and affect the anterior region of the mandible.6

Destructive lesions in the craniofacial region, especially in the jawbones, if associated with giant cells, include a spectrum of lesions that pose difficulty in diagnosis. The nature of such a lesion in the jawbones is questionable about whether it is a reactive/benign lesion or aggressive/non-aggressive. Clinical, radiological and histopathological correlation may be a reliable indicator to differentiate between the qualities of the lesion which directly accounts for effective and individual planning of the treatment. Herein, we report a case of a giant cell containing an aggressive lesion in the anterior mandible, and along with this, we have discussed the differentiating features of central giant cell granuloma (CGCG) from the neoplastic giant cell tumour (GCT).

Case presentation

A female patient in her late 20s reported a painless swelling over the left lower back tooth region for the past 2 months. She gave a history of a road traffic accident, causing blunt trauma to the chin area 2 weeks ago, after which she noticed a gradual increase in the size of the swelling associated with the mobility of teeth. She also revealed a history of systemic lupus erythematosus for the past 4 years and had been under steroid medication for the same. Also, she gave a history of tuberculous lymphadenopathy 2 years ago. Extraorally, facial asymmetry was noticed on the left side, because of intraoral swelling and palpable submandibular lymph nodes. Intraorally, a diffuse swelling of size 5×4 cm was extending anteroposteriorly from the left lower central incisor to the left lower II molar tooth region with buccal and lingual cortical plate expansion. The mucosa covering the swelling appears to be ulcerated in one area, which was covered with necrotic slough. Lingual vestibular obliteration was evident on palpation; the swelling was soft, non-tender, smooth and not mobile. There was paresthesia on the left side of the lower lip. There was grade III mobility evident from the left lower central incisor to the left lower II molar teeth with tenderness on percussion of teeth from the left lower lateral incisor to the left lower II premolar tooth (figure 1).

Figure 1

Diffuse intraoral swelling of size 5×4 cm anteroposteriorly from 31 to 37 tooth region with buccal and lingual cortical plate expansion.

Investigations

Orthopantomogram revealed a well-defined multilocular radiolucency involving the periapical region of the root canal-treated right lower central incisor and extending until the mesial aspect of left lower I molar tooth, which was well evident above the inferior alveolar canal. The divergence of roots was noted concerning the left lower canine and II premolar teeth along with marked root resorption in the left lower I premolar teeth and apical root resorption in the left lower II premolar teeth (figure 2). Cone-beam CT concerning the anterior mandible revealed well-defined radiolucency extending from the mesial aspect of left lower I molar teeth to the mesial aspect of left II premolar teeth with complete loss of buccal and lingual cortical plate along expansion (figures 3 and 4). Based on clinical and radiographic features, it was provisionally diagnosed as odontogenic cyst, probably odontogenic keratocyst. Differential diagnoses of aneurysmal bone cyst, traumatic bone cyst and odontogenic tumours were considered. On incisional biopsy, histopathology exhibited highly cellular and proliferative fibroblastic areas within the connective tissue. These fibroblastic cells exhibited spindle-shaped morphology with oval to spindle-shaped nucleus. Some of the areas of connective tissue exhibited hyalinisation resembling stromal fibrosis. Within this background of connective tissue, there was an infiltration by plenty of giant cells with variable sizes. Some of these giant cells were mononucleated but most were multinucleated, present diffusely throughout the connective tissue. Focally, highly active fibroblastic areas with plenty of MGCs were noticed. Apart from this, numerous blood vessels and spicules of woven bone were also seen (figure 5A–D). Based on the histopathological features, it was diagnosed as CGCG.

Figure 2

Orthopantamogram showing a well-defined multilocular radiolucency involving the periapical region of right lower central incisor extending to the mesial aspect of left lower I molar tooth is evident well above the inferior alveolar canal; divergence of roots noted in relation to left lower canine and II premolar teeth, marked root resorption, extending to the middle third of the root noted in left lower I premolar region and apical root resorption in left lower II premolar region.

Figure 3

Cone-beam CT (CBCT) panoramic image and CBCT reconstructed (three-dimensional format) anterior and posterior view showing well-defined radiolucent areas with complete loss of alveolar bone from 35 region to 44 teeth region and floating of 34, 33, 32, 31, 41, 42 teeth. There is evidence of inferior alveolar nerve on both sides of mandible.

Figure 4

Cone-beam CT axial view of mandible towards apical region shows complete bone loss in buccal and lingual cortex with expansion.

Figure 5

(A–D) Photomicrograph showing lesional areas, highly cellular with proliferation of ovoid to spindle-shaped stromal cells along with presence of plenty of mononucleated and multinucleated giant cells (A,B). Lesional area is surrounded by fibrous capsule; haemorrhagic areas, extravasated red blood cells and bone were noticed (A) (H&E 10×). Highly proliferative stromal tissue with blood vessels and inflammatory cells (H&E 40×) (C). Immunopositivity for CD68 on multinucleated giant cells and individual mononuclear cells (immunohistochemistry 10×) (D).

Differential diagnosis

Giant cells of CGCG should be differentiated from other giant cell lesions such as GCT, brown tumour of hyperparathyroidism, aneurysmal bone cyst, cherubism and other osteolytic giant cell-associated lesions of the jaw.4 The diagnostic features of CGCG are uneven distribution of MGCs clearly arranged in recognisable clusters separated by scar-like stromal tissue. The giant cell clusters will be particularly evident in areas of haemorrhage. In the periphery of the lesion, newly formed reactive trabecular bone formation may be extensive and may obscure the other elements of the lesion.7 8 The present case was consistent with the diagnostic criteria of CGCG. Also on immunohistochemistry, it showed immunopositivity for CD68 for MGCs and individual mononuclear cells (figure 5D), which confirmed the final diagnosis of CGCG.

Treatment

En bloc resection of the mandible with tooth-bearing alveolus and part of the basal bone from the right lower lateral incisor to left lower II premolar was done followed by chemical cauterisation with Carnoy’s solution and enucleation of the CGCG lesion. For reconstruction, the lower border of the mandible having healthy bone was adapted with a 2 mm 15-hole long plate and fixed with screws of 2×8 mm. Bone graft (novograft), along with xenograft mixed with platelet-rich fibrin, was placed and sutured over the defect (figure 6). The diagnosis of the excisional specimen received for histopathological examination was consistent with that of the incisional biopsy (figure 7A–D).

Figure 6

Surgical picture showing en bloc resection of mandible with tooth-bearing alveolus, and part of basal bone from 42 to 35 was removed.

Figure 7

(A–D) Photomicrograph showing the dense fibrous tissue with areas of spindle-shaped mesenchymal cells and areas of osteoid formation and areas of fibrohistiocytic appearance (A). Stromal cells appear to be highly active with blood vessels and inflammatory cells (B). Multinucleated giant cells in lumen of blood vessels (C) (H&E 40×), and areas of bony resorption noticed (D) (H&E 40×).

Discussion

The condition of the patient after surgery was stable (figure 8). Further follow-up for a period of 6 months was done without any sign of recurrence.

Figure 8

Postoperative panoramic image showing partially edentulous arch with loss of 35, 34, 33, 32, 31, 41, 42 teeth; along with this, bone plating was done in the mandible anterior region.

The CGCG is an MGC-rich intramedullary bone lesion with unclear aetiology.9 In 1953, Jaffe introduced the term ‘giant cell reparative granuloma of jawbones’ to differentiate its less aggressive nature from GCTs of bones citing its clinical and histopathological differences.4 10 Currently, the word ‘reparative’ was not accepted due to the destructive behaviour of CGCG.4 In 1959, Austin et al agreed that these two lesions were histopathologically distinguishable entities and that GCT is rare in jaws.11 Lucas in 1972 stated that the giant cells in the CGCG are often smaller than the giant cells of the neoplasm and are unevenly distributed throughout the lesion, whereas in the neoplasm, numerous evenly distributed giant cells are present in practically every field.12 In CGCGs, spindle-shaped mononuclear cells can secrete RANKL, which promotes the formation of MGCs with an osteoclast phenotype9 (table 1).

Table 1

Giant cell tumour versus central giant cell granuloma4 6–12

CGCG histogenesis was still controversial and debated regarding whether it represents a reactive, an inflammatory or a neoplastic process.13 The vascular theory of hypothesis suggests that CGCG belongs to the spectrum of mesenchymal proliferative vascular primary jaw lesions. Activated macrophages/monocytes release the vascular endothelial growth factor and basic fibroblast growth factor, which are potent inducers of angiogenesis.14

CGCG was thought to be a reactive or reparative process to intraosseous haemorrhages with subsequent inflammation.8 Trauma was found to be an important aetiological factor for the initiation of CGCG. The progression of subsequent lesions happened by the accumulation of tissue by slow, minute, multicentric haemorrhages with some defect in capillaries. The WHO has defined it as ‘an intraosseous lesion consisting of cellular fibrous tissue that contains multiple foci of haemorrhage, aggregations of MGCs and occasionally trabeculae of woven bone.15 However, due to its undetermined, occasional aggressive behaviour and its possible relationship to GCTs of long bones, CGCG is now considered a benign neoplasm.16

Giant cell granuloma may be central or peripheral type. The central type occurs as a smooth endosteal lesion, clinically presents as asymptomatic, slow-growing, occasionally fast-growing swelling, undetected until it causes facial deformity, impaired nasal breathing, loosening or displacement of teeth. The peripheral lesion occurs as a sessile or pedunculated lesion on the gingiva.17 However, in the present case, the patient experienced rapid growth of the lesion secondary to trauma, intrabony lesion causing mobility and displacement of teeth, and root resorption describing the aggressiveness of the lesion. The literature stated that the lesion is usually rubbery/elastic on palpation because of thinning of the cortical plate, expansive and invasive it never grows around or invade nerve trunks, perineural sheaths and perineural space.18 However, the present case was consistent with the existing literature review except for the neural involvement where the patient had symptoms of paraesthesia.

CGCG of the jawbones may be categorised into a non-aggressive and aggressive lesion, based on the clinical and radiographic features. Non-aggressive lesions are slow growing, relatively small, usually asymptomatic and do not cause cortical perforation or root resorption. There will be accidental findings during a routine radiographic examination or as a result of painless jaw expansion and the chance for recurrence will be low. Aggressive lesions are characterised by large, painful, rapid growth that usually causes tooth displacement, root resorption, cortical perforation and/or paresthesia. Extension into soft tissue and ulceration of the overlying mucosal surface are also possible.19 20

Radiographically, the CGCG appears as a unilocular or multilocular radiolucency, with sharply delineated but generally non-corticated borders. Sometimes, faint calcifications are noticed because of poorly mineralised osteoid bone within the lesion. The lesion may vary from a 5 mm incidental radiographic finding to a destructive lesion greater than 10 cm. Small unilocular lesions may be confused with periapical granulomas or cysts, and multilocular lesions may appear similar to ameloblastomas.20

Histopathologically, it is a benign proliferation of mononuclear spindled-shaped fibroblasts and MGCs. The primary tumour cells of CGCG are fibroblasts that make up the proliferative component of CGCG and express positivity for Ki67, which is indicative of the cells in the cell cycle. In CGCG, spindle-shaped mononuclear fibroblasts secrete RANKL, the protein which promotes the MGC formation with an osteoclast phenotype. The key features are MGCs, usually arranged in clusters separated by scar-like stromal tissue. The MGCs and their clusters are uneven in distribution and particularly evident in areas of haemorrhage. The accessory cells such as macrophages, dendrocytes, endothelial cells and extravasated red blood cells were also noticed.8 9 11

However, immunohistochemistry is unreliable in reaching a diagnosis of CGCG; the osteoclasts and their precursors are immunoreactive for CD68, CD45 and tartrate-resistant acid phosphate. The current case also showed nuclear positivity for CD68.21 22

The treatment of choice for CGCG is surgical enucleation and curettage which was also carried out in the current case. Combined curettage and cryotherapy may reduce the recurrence rate by 50% in non-facial bones. Radiation has been used as a therapeutic modality, but the subsequent development of sarcoma has been reported. Segmental resection is advocated only in case of multiple recurrences or extensions to overlying tissues.18 23 24

Whitaker and Waldron in 1993 proposed that CGCG and GCT belong to the same spectrum of lesions and their aggressive behaviour is reminiscent of each other. But it is still believed that GCT should be distinct from other giant cell lesions, particularly CGCG, which is considered to have a lower recurrence rate and with no report of metastases.20 The aggressive nature of the present case may be due to the growth phase of young age, hormonal influences, exuberant healing reaction after trauma similar to hypertrophic scar with keloid formation or it can be due to intake of steroid medication which has an anti-inflammatory effect and its tissue growth-promoting nature. CGCG can also be present with aggressive nature in tissues resembling GCT. The site of the lesion and histopathology helped in diagnosis which is essential for treatment planning and assessing the prognosis. The clinical team should be aware of the aggressive nature of CGCG for providing appropriate management.

Patient’s perspective

Initially, I felt it was swelling might be because of a tooth cavity or something else. I visited the doctor and they asked me for some history of swelling and they asked to take x-ray photos and tissue samples. I was shocked to hear that something like a tumor was inside my bone and need to do surgery under general anesthesia. I am very scared to do surgery but they treated me very well after surgery I felt pain and they gave me medication to relieve the pain. At the time of discharge, I had slight swelling at the site of the operation. I revisited the dental hospital after one week and they gave assurance that it was healed properly. Still, now I haven’t any issues.

Learning points

  • The aggressive behaviour of central giant cell granuloma (CGCG) is reminiscent of giant cell tumour (GCT) of bones. However, it is still believed that GCT should be distinct from other giant cell lesions, particularly CGCG, which is considered to have a lower recurrence rate and with no report of metastases.

  • To do successful management of CGCG, it is necessary to rule out other giant cell neoplasms.

  • The interdisciplinary approach using radiographs, tissue examination and other biochemical investigations (serum calcium, alkaline phosphatase, parathormone level, etc) can help to rule out metabolic disorders and reach a conclusive and confirmatory diagnosis.

  • Since children and young adults are most commonly affected, early diagnosis and definitive management could avoid extensive cosmetic deformity, functional disability and also the chance of recurrences.

Ethics statements

Patient consent for publication

Acknowledgments

We like to acknowledge Dr Sathya Narayanan, Professor and Head, Department of Oral and Maxillofacial Surgery, Indira Gandhi Institute of Dental Sciences, Sri Balaji Vidyapeeth, who has performed surgical procedure for this patient but who has not been recognised as a contributor, as well as for personal expressions of gratitude.

Footnotes

  • Contributors UG and BK gathered the clinical data including the photograph after gaining written consent from the patient. SDA and UG contributed equally to writing the paper following planning, researching and interpreting the results. Hence, SDA is considered as the first author. BK, UG and SM contributed to writing the paper, editing, optimising the image and submitting the paper.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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