1

Introduction

Giant cell-rich lesions of bone is a heterogeneous group of multinucleated giant cell proliferation lesions of osteoclastic type. Giant cell granulomas (GCGs), cherubism, aneurysmal bone cyst (KOA), and brown hyperparathyroidism tumor (BHT) are commonly found in the oral and maxillofacial region [ ].

GCG was first described by Jaffe in 1953 as an idiopathic non-neoplastic proliferative intraosseous lesion consisting of cellular fibrous tissue that contains multiple foci of haemorrhage, aggregations of multinucleated giant cells and occasionally trabeculae of woven bone [ ]. The term giant cell reparative granuloma is now abandoned because the lesion represents essentially a destructive process [ ]. The 2017 WHO classification of odontogenic and maxillofacial bone tumors categorize GCG among “giant cell lesions and bone cysts,” with a distinction between its central (intraosseous) and peripheral (soft tissue-dependent) form [ ]. Surgery is the treatment of choice of GCG, but is associated with a risk of functional impairement and disfigurement in the maxillofacial region [ ]. Alternative therapies such as intralesional injections of corticosteroids, calcitonine, biphosphonates or interferon-alpha were used to treat GCG, aiming to avoid a mutilating surgery [ ].

We herein describe a case of extensive aggressive central giant cell granuloma (CGCG) of the maxilla in a 11 years old female, treated with neoadjuvant intralesional corticosteroid injections followed by curretage of the remaining mass.

2

Case report

An 11-year-old female presented to our department of Oral and maxillofacial surgery for a maxillary swelling that appeared 4 months prior to admission. The parents had a history of consanguinity, and her 16 year old older sister is presenting craniofacial dysmorphia and short stature that were not investigated ( Fig. 1 ).

Picture of our patient (left) and her sister (right) both presenting short stature and facial dysmorphia.

Physical examination revealed a short stature and a craniofacial dysmorphia constituted by frontal bossing, midfacial hypoplasia and a left cheek tender swelling with a partial left nasal obstruction. Oral examination showed an extensive painful left maxillary burgeoning mass extending to the right maxilla, with a total dental architecture disruptment ( Fig. 2 ). Facial CT scan showed an extensive lesion of tissular density involving both maxillary bones, with extension to the left nasal cavity, and osteolysis of left palate, lateral and medial left maxillary walls ( Fig. 3 ). A biopsy was performed, and the results were consistent with giant cell granuloma. Pycnodysostosis was suspected by the pediatricians upon family history, physical and radiological findings, and is yet under investigation.

Picture at admission showing extensive lesion centered on the left maxilla, extending to the left maxilla and oral cavity.

CT scan at admission showing tissular lesion of both maxillary bones with bony destruction.

Due to the extensive lesion and the risk of deformity associated with surgical intervention, neoadjuvant therapy consisting of intralesional methylprednisolone injections was started. The regimen consisted of a bi-weekly intralesional injections of 1 mL of methylprednisolone per cubic centimeter of radiolucency. An impressive reduction of the mass was observed ( Fig. 4 a), and curettage of the remaining lesion was performed under general anesthesia ( Fig. 4 b).

A. clinical examination after 6 weeks of intralesional injections of corticosteroids. B: Intra-operative picture of curettage of the remaining mass.

The patient was discharged in good health, but regular check-up appointments were not rigorously observed due to the patient’s geographic remoteness. She consulted 7 months after the surgery for recurrence of the granuloma confirmed by histopatological examination of a biopsy specimen. The same regimen of intralesional injections of methylprednisolone followed by curettage were conducted. The patient showed no signs of recurrence after 29 months of follow-up ( Fig. 5 ).

Picture of most recent examination, 29 months after treatment.

3

Discussion

CGCGs represents 7 %–10 % of all benign tumors of the jawbones [ , ]. An incidence rate of 1.1/million population of CGCG was calculated in the Dutch population [ ]. It appears to have a female predilection with a 2:1 ratio, involving most frequently patients under the age of 30 years with a peak of age incidence between 10 and 24 years and a higher frequency in the mandible [ , ].

The etiology of GCG is yet under investigation. It was considered to be a reparative reaction to trauma but the lack of trauma history among patients made authors suggest other theories [ , ]. Infectious processes, developmental disturbances, genetic etiologies and inflammatory causes have been brought forward [ , ]. Additionally, the predisposition of younger individuals to CGCG formation have been linked to the actively developing craniofacial skeleton wich includes osteogenesis and exfoliation and eruption of teeth which ceases in adulthood [ ]. On the other hand, cases of multiple concurrent CGCG are associated with inherited syndromes involving the RAS/MAPK pathway called RASopathies such as Noonan, LEOPARD or Costello syndromes [ ]. To our knowledge, no GCG was associated with pycnodysostosis.

The jawbones are the most common localisation of CGCG, but occurrences in hard palate, orbital region, para nasal sinus, nasal cavity and septum, metacarpal bones and phalanges have been reported in the litterature [ , , ]. A widely accepted classification of CGCG have been proposed by Chuong et al. [ ] It distinguishes aggressive and nonagressive lesions based on clinical features. Aggressive lesions were caracterized by pain, rapid growth, swelling, root resorption, cortical perforation and a high reccurrence rate.

The maxillary localisation of CGCG inflicts special considerations. The cancellous nature of the maxillary bone and the thin cortical plate of the maxilla facilitates the expansion of the lesion to important structures such as the maxillary sinus, nose, orbit and cranial base. This clinically translates to diplopia, epiphora, and epistaxis or dysphagia, nasal obstruction and facial disfigurement such as described in our case [ , , ].

Radiological findings of CGCG vary in the litterature with two distinct presentations being described; an unilocular, radiolucent cyst-like lesion and a multilocular cyst-like lesion with a bubble appearance with no significant distinction found between maxillary of mandibular CGCGs [ , ]. In pediatric patients, especially in the mixed-dentition period, superimpositions of anatomic structures frequently occur and the radiographic diagnosis may be challenging. CT scan is therefore recommended in the diagnosis workup of GCG. CT scan usually shows the lesion, the bony involvement and the extension toward important adjacent anatomic structures such as the maxillary sinus, nose, orbit and cranial base [ , , ].

Microscopic examination of giant cell granulomas shows numerous multinucleated giant cells surrounded by spindle shaped cells (fibroblast and histiocyte-like cells and monocyte-macrophages) within a prominent fibrous stroma [ ]. These giant cells have a patchy distribution and signs of bleeding into the mass, and deposits of hemosidrin are frequently seen. Sparse strands of collagen fibres partly subdivide the lesion which may contain a few trabeculae of osteoid or bone [ ].

Due to its lack of pathognomonic characteristics, CGC can mimick several conditions. It must be ditinguished from cherubism, an autosomal dominant disorder characterized by bilateral expansion of the mandible and/or the maxilla within the first few years of life, presenting multifocal and multilocular cystic lesions of the jaws with similar histologic findings as GCGs [ , ].

When assessing the diagnosis of CGCG, practicians should also bring forth the diagnosis of giant cell tumor (GCT) as both share various clinical and radiological features. However, CGCG can be differentiated from GCT on the histopathologic exam as CGCG have relatively fewer multinucleated giant cells than GCT with increased incidence of osteoid, fresh hemorrhages and hemosiderin deposits while the giant cells are more evenly distributed in GCT and features cell necrosis [ ]. Differentiating between the two conditions can be challenging as a considerable overlap of characteristics can occur between these two lesions. This lead some authors to suggest that CGCG and GCT may be a part of a spectrum of a single condition evolving in a continuum [ ].

Other differential diagnosis of CGCG include aneurysmal bone cyst, benign chondroblastoma, brown tumor of hyperparathyroidism, fibrous dysplasia, non-osteogenic fibroma, and osteosarcoma [ , , , ].

Surgery is the treatment of choice for CGCG with several procedures described: enucleation, curettage, peripheral ostectomy and en bloc resection [ , ]. Practicians must keep in mind the tendency of CGCG for recurrence, and given the fact that the recurrence of this lesion is not associated with serious consequences as seen with the recurrence of aggressive tumors such as ameloblastoma, some authors recommend curettage rather than enbloc resection even for aggressive CGCG [ , ]. Nontheless, surgery for aggressive lesions may sacrifice ajdacent structures affecting function and resulting in various degrees of deformity [ ]. Consequently, considering alternative therapies, as initial or adjuvent treatment, is essential for reducing the surgery associated morbidity.

Jacoway & al were the first to suggest injections of corticosteroids as a non surgical treatment for GCG on the basis that corticosteroids should inhibit macrophages differentiation and activity [ ]. Intralesional corticosteroid injections has since showed it’s efficiency in the treatment of GCG. Advantages of corticosteroids treatment include a lower cost, avoidance of compromising vital and functional structures especially in treating young patients and hence prevent the long term sequelae associated with a surgical intervention, although patients suffering from diabetes, infections, immunodepression and pregnant patients are not suitable for this method [ ].

Corticosteroids can be combined with surgical treatment such as in our case, or in combination with other treatment options such as biphosphonates or calcitonin. However,it’s association with biphosphonates could result in medication related osteonecrosis of the jaw [ ].

Bisphosphonates are widely used to inhibit osteolysis and osteoclasts’ activity in osteoporosis, Paget’s disease, and metastatic cancer and its use as an alternative treatment for CGCG have only been reported in a few case reports. Calcitonin is a Thyroid c cells produced hormone, it inhibits osteoclastic activity of giant cells thus justifiying its use in CGCG [ ]. Interferon-alpha is a cytokine with antiangiogenic properties for which a prolifrative lesion as CGCG could respond [ ]. However, in the cases reported in the litterature additional therapy was indicated [ , ].

Denosumab and Imatinib were also suggested as alternative modalities but are lacking clinical evidence to support their use [ , ].

CGC lesions of the jaw are associated with a significantly high recurrence rate, which varies between 7.8 % and 72 % [ ]. A higher recurrence rate is generally associated with clinical and radiological aggressiveness [ , ] and younger age [ , ], but there is no sufficient data to affirm the existence of a higher recurrence risk in patients with maxillary locations or in those treated by medical procedures exclusively. Overall, the disease-free rate varies between 93.2 % the first year and 76,1 % the fifth year [ ], which implicates the importance of a long-term surveillance.

4

Conclusion

Though classified as a benign tumour, GCGs can have serious functional and morphological consequences or even life-threatening repercussions if vital structures such as airways are involved. Surgical treatment is the gold standard for treatment of GCGs and alternative therapies are enriching the therapeutic arsenal which can be of crucial help if the surgical procedure might be mutilating. Further specific studies are nonetheless necessary to gain significant data regarding those therapies.

Formatting of funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

El Hamid Sami: Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Ilhami Ouail: Supervision. Razem Bahaa: Data curation, Conceptualization. Oukerroum Abdelhakim: Validation. Slimani Faiçal: Validation.