Giant cell reparative granuloma originating from the ethmoid sinus

1. Introduction 

Giant cell granuloma is not a true neoplasm but a reactive tumor that develops after the inflammatory process following the intraosseous hemorrhage [1]. It may be difficult to differentiate it from the other giant cell lesions with similar histological appearance and clinical course. Aneurismal bone cyst, giant cell tumor (osteoclastoma) and Brown tumor characterized by hyperparathyroidism are the lesions that must be included in the differential diagnosis [2], [3].

Mandible and maxilla are the primary regions of involvement in the head and neck in cases with giant cell granuloma [3]. Only a small number of cases have been reported with the involvement of the paranasal sinuses and the orbit. In this paper, an aggressive giant cell reparative granuloma originating from the ethmoid sinus is presented and the criteria for the differential diagnosis are noted in the light of the histological, clinical and biochemical parameters and the literature is reviewed.

2. Case report 

A 7-year-old boy was admitted to ophthalmology policlinic with the complaint of swelling of his right eye, nasal obstruction and bleeding of the nose. Erythema and swelling of the eye began 4 weeks before the admission and was treated by local eye drops. Antibiotics (amoxicilline-clavulanic acid) were administered due to enlargement of the swelling towards the middle face and the nose. There was no response to the treatment and the patient was sent to our hospital. The otorhinolaryngological examination revealed a mass that completely obstructed the right nasal cavity. The outer surface of the mass was smooth and it displaced the nasal septum towards the left side. There was proptosis of the right eye in addition to swelling and erythema of periorbital and maxillozygomatic regions being most prominent on the medial canthus. There were no palpable masses or lymphadenopathies in the neck. Other systemic examinations were in the normal limits. A slight leucocytosis (WBC: 12 800 10e3/Ul; lymphocytes 27.1%, monocytes 6.1%, granulocytes 66.8%) was evident on the complete blood count in addition to anemia (Hb: 9.2 g/dl; Hct: 27.3%). The blood chemistry and the chest X-ray were normal. A solid mass with smooth margins that filled the right ethmoid sinus, eroded the lamina papyracea, reached the medial rectus and optic nerve and caused the destruction of the posterior table of the frontal sinus was seen on the computed tomography (CT) (Fig. 1). No intracranial invasion was evident on the magnetic resonance imaging (MRI).

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Fig. 1. The tumor as seen on the CT before the first operation.

The mass was biopsied endoscopically. The histopathological diagnosis was central giant cell granuloma (reparative giant cell granuloma). Serum parathormone (PTH), Ca and P levels were in normal limits [(PTH: 1.26 pmol/l (0.8–6.4), Ca: 8.94 mg/dl (8.1–10.4), P: 4.34 mg/dl (2.6–4.5)]. Parenteral antibiotics (ampisilline-sulbactam 1 g/day iv) were administered to the patient and surgery was performed. The lateral rhinotomy incision was enlarged with an infraciliary incision and a temporary tarsorraphy was made. The mass originated from the localization of the ethmoid sinus and eroded the lamina papyracea, medial orbital floor, medial and anterior walls of the maxillary sinus and anterior part of the ethmoid roof. It filled the right nasal cavity and deviated the nasal septum towards the left side. It pushed the medial rectus and the optic nerve laterally and reached the anterior wall of the sphenoid sinus. The mass was freed from the surroundings with blunt dissection and was excised en bloc (Fig. 2). There was no enophthalmus or amblyopia in the postoperative period. Acuity of vision was better compared with the preoperative period (preoperative right: 0.5, left: full; postoperative right: 0.7–0.8, left: full).

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Fig. 2. The tumor mass excised en bloc in the first operation.

The histopathologic diagnosis of the tumor mass confirmed the endoscopic biopsy as reparative giant cell granuloma (Fig. 3).

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Fig. 3. Histologic appearance of the tumor mass showing giant cells related to vascular spaces in a cell-rich stroma and reactive bone formation. (H.e. ×200).

Six weeks after the discharge, the patient admitted with the similar complaints such as proptosis of the right eye and epistaxis. After physical examination and the radiological imaging, the recurrence of the mass was noted and a surgical operation was performed. There was a large bony defect on the ethmoid roof and the anterior wall of the sphenoid sinus. A wide bony destruction including the inferior orbital wall in addition to medial orbital wall was noted. (Fig. 4) The mass was excised en bloc.

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Fig. 4. MRI of the tumor recurrence after the first operation.

Proptosis and epistaxis recurred 3 weeks after the surgery. The recurrence of the mass was evident. The patient was consulted with the pediatric medical oncology department and he was undertaken the anti-angiogenic treatment protocol. His therapy is still carried on.

3. Discussion 

Jaffe is the first who made a note of the giant cell lesions that were well circumscribed, benign and localized in the jaws and used the term ‘giant cell granuloma’ [1]. The granuloma formation is called reparative due to invasion and injury of the surrounding structures [2]. Bullock and Luck reported that these lesions could be seen in bones of the face and maxilla in addition to the jaw [3]. In head and neck, the giant cell reparative granulomas usually involve the jaws, however, cases with the involvement of the nasal septum, cranial base, temporal bone and paranasal sinuses have been reported [4], [5], [6], [7], [8], [9], [10], [11], [12]. Tubular bones of the hands and the feet may also be involved although the involvement of the bones other than craniofacial bones is rare [13].

It is difficult to differentiate the lesions originating from ethmoid sinus from the lesions coming from other paranasal sinuses. Due to local destructive behavior and aggressive course, other paranasal sinuses and the orbit is usually involved and solitary ethmoid sinus involvement is reported in only one case [14].

The etiology of giant cell reparative granuloma is uncertain but the role of the trauma has been questioned. The investigators stated that chronic sinusitis might play a role in the involvement of the paranasal sinuses. As Koay et al. stated after the theory of Hirschl and Kalz, chronic infection of the paranasal sinuses cause local hemodynamic alterations and as a result, this factor initiates the reactive proliferative process causing microhemorrhages. This leads to progressive granuloma formations in some patients [6], [14].

The symptoms related to giant cell reparative granuloma may vary and may arise in a few weeks or years owing to aggressiveness and extent of the lesion. Nasal obstruction, bleeding, smelling disorders, swelling of the face, headache, diplopia, proptosis, ophtalmoplegia, blindness, and disorders related to cranial nerve involvement can be encountered [12], [14].

In our case there was no chronic inflammation or trauma in the clinical history. Having a severe acute onset, clinical symptoms and radiologic findings presented a very agressive behavior.

Giant cell reparative granuloma is appraised in two clinical forms as central-endosteal and peripheral-soft tissue forms [15]. The central type can be seen in all ages, however, it is usually encountered between the ages of 10–20 years and with the involvement of the mandible. The maxilla, ethmoid, sphenoid, and temporal bone involvement has also been reported [6]. Peripheral type is encountered in women below 30 years of age and it frequently involves oral cavity, anterior gingival mucosa and alveolar mucosa. This group is called giant cell epulis and recurrences or progression is reported during the pregnancy [9], [16].

There is no histological difference between central and peripheral giant cell reparative granulomas. Giant cells related to vascular spaces in a cell-rich fibroblastic stroma, low mitotic activity, cyst formation and reactive bone formation are major components of the histological appearance (Fig. 3). The lesions with similar histopathological appearance as aneurismal bone cyst, giant cell tumor (osteoclastoma) and Brown tumor characterized by hyperparathyroidism must be included in the differential diagnosis [6], [15]. Aneurismal bone cysts are cystic soft tissue masses that involve frequently the vertebrae and the long bones. The involvement of the jaws and the facial bones is rare. They usually arise following trauma or local hemodynamic alterations in children and adolescents. They consist of fibroblasts, giant cells and osteoid trabecules in a septal stroma and can be confused with the giant cell reparative granuloma [17]. Giant cell tumors are usually seen in the 3–4th decades and they usually involve the epiphysis of the long bones. The involvement of the ethmoid sinus, sphenoid sinus and the temporal bone are rare. The histological differential diagnosis is accomplished with the absence of both the chondroid matrix and the new bone formation. They have a local aggressive course, recur frequently and may cause distant metastasis [18]. Ca, P and PTH levels are in normal limits in giant cell reparative granuloma, aneurismal bone cyst and giant cell tumor (osteoclastoma) and they can be differentiated from the Brown tumor using these parameters since this tumor is accompanied by hyperparathyroidism.

No metastasis or malignant transformation is observed in the clinical course of the giant cell reparative granuloma. The common proposal for the treatment is surgical excision or curettage and 80% of the cases can be cured with these modalities. Surgical excision is curative and the healing takes place with new bone formation and sclerosis. However, it must be kept in mind that a craniofacial resection may be needed for progressive giant cell reparative granulomas with intracranial involvement [9], [12], [14].

Since the lesion is usually extensive, recurrence due to incomplete resection may be observed in 4–12% of the cases [19]. Radiotherapy may be suggested in the case of recurrence or unresectable tumor, however, it should be noted that some cases are radioresistant and a sarcomatous transformation may take place in long term [11], [14].

Nowadays, the anti-angiogenic therapy is recommended for especially recurrent cases [20]. Interferon alpha-2a inhibits the angiogenesis and was discovered following a sequence of laboratory investigations at the end of 1980s. It is used successfully for the treatment of life threatening hemangiomas and vascular tumors of different organs. Collins reported that anti-angiogenic therapy brought about quite successful results in the cases with giant cell reparative granulomas [21].

In our patient a second surgical operation was carried out due to tumor recurrence 6 weeks after the total surgical excision. The bone destruction and the tumor mass were greater compared with the first operation. The tumor recurred for the third time 4 weeks after the second surgery. The anti-angiogenic treatment protocol was preferred to radiotherapy due to variability of the effectiveness radiotherapy on the giant cell granuloma and the risk of sarcomatous transformation because of radiotherapy. Our patient is still on anti-angiogenic therapy.