Central giant cell granulomas of the jaws regress with calcitonin therapy

Central giant cell granulomas of the jaws regress with calcitonin therapy M. Harris

Joint Department of’.Muxill~fi(ciuI Surgery und Oral Medicine, The Eastman Dentul and University College Hospit&, London

SUMMA

R Y. Aggressive central giant cell granulomas may be eliminated by administering human calcitonin 0.5 mg (100 iu) deep subcutaneously for 1 year. This avoids the need for mutilating surgery or radiotherapy in growing children. Aggressive recurrent peripheral lesions (the giant cell epulis) can also be treated by excision after calcitonin therapy. These giant cell granulomas should be redefined as osteoclast granulomas, and the aneurysmal bone cyst, the cystic osteoclast granuloma. However the stimulus for the disturbance in the osteo progenitor spindle cell needs to be defined.

INTRODUCTION

rate for the central lesion is said to be low. However, this is at variance with known cast presentations and may reflect the difficulty of assessing the outcome of unpublished unsuccessfully treated single cases. At least 26% of aneurysmal bone cysts appear to recur after curettage (Deeb et al., 1980). However as both central lesions usually occur in young patients, even simple curettage necessitates dental extractions and produces varying degrees of deformity. Unfortunately, large lesions and recurrent lesions arc treated by excision of the mandible or maxilla. These lesions do not regress naturally, and untreated lesions may be seen in third world countries where they continue to enlarge into early adult life and produce gross deformity. Hence the need for non-surgical management. The uncontrolled use of calcitonin in the three central lesions described in this paper was based on the hypothesis that the giant cells were osteoclasts and therefore would be immobilised by calcitonin, and so allow the destructive granulomatous lesion to heal until the idiopathic stimulus had ceased.

The central and peripheral giant cell granulomas of the jaws are uncotrmon and ill understood. They contain multinucleate giant cells which arc usually associated with areas of hacmorrhage or blood vessels in a loose vascular stroma of plump spindle cells. These lesions are not encapsulated and osteoid or new bone are seen between the granulomatous areas. The aneurysmal bone cyst appears to bc a cystic version of the central lesion, but is more frequently found elsewhere in the skeleton. Jaffe (I 953) determined that the intraosseous giant ccl1 lesion was not a tumour but a reactive granuloma. Later Bernier and Cahn (1954) rationalised the similarities bctwccn the central lesion and the giant cell epulis and created the designation of central and pcriphcral giant cell reparative granulomas. However, they are no longer considered to be reparative. As both are histologically indistinguishable from the comparable lesions occurring in hyperparathyroidism, it is mandatory to establish that the serum Ca, phosphate, alkaline phosphatase, iPTH are normal to confirm a diagnosis of the idiopathic lesion. The central granuloma and its cystic counterpart the aneurysmal bone cyst tend to occur in young patients in the second decade with a slightly increased incidence in females (Waldron & Shafer, 1966). The aneurysmal bone cyst is rare and only 3-12% occur in the craniofacial s’teleton. The most common site is the mandible followed by the maxilla (Salzman & Jun, 1981). The idiopathic cpulis (peripheral giant cell granuloma) also tends to be slightly more common in females than males (6:4) but occurs at any age with a maximum incidence between 40 and 60 years (Katsikeris, 1988). Treatment hitherto has been by curettage or resection of the central lesion and excision of the cpulis. A recurrence rate of 10% for the epulis has been recorded which is trsually attributed to a failure to eliminate local irritation. The published recurrence

PATIENTS

AND METHODS

Three children with central lesions and one adult with an aggressively recurrent peripheral granuloma were treated with an empirical dose of 100 iu (0.5 mg) calcitonin injected subcutaneously daily. Case reports

Case I An I l-year-old Greek girl prcscnted with a painless swelling in the right anterior palate and ipsilateral nasal obstruction of 2 months duration. The histology was that of a central giant cell granuloma. Her serum Ca, corrected for albumin was 2.46 (2.15-2.65) mmol;l, phosphate 1.76 mmol!l (0.8-1.4), alkaline phosphatase 182 iu:‘l (< 360 for age), plasma FTH 240 rig/l ( < 730) and calcitonin I20 rig/l ( < 150 for age). Radiographs and a CT scan showed a mixed 89

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opaque and luccnt lesion extending upwards into the floor of the nose with complete obstruction on the right airway. Curettage would have nccessitatcd the removal of her premaxilla and nasal floor. She was given 0.5 mg (100 i.u) of synthetic human calcitonin (Cibacalcin) by subcutaneous injection daily for 6 months, at which time the swelling seemed to be unchanged. A palatal flap was reflected and a cavity was found containing serum and some soft granulation tissue which was removed for histology. This reconfirmed the diagnosis of a giant cell granuloma. Blood chemistry showed strum Ca 2.36 mmolil, phosphate 1.64 mmol/l, alkaline phosphatasc 173 iu/l and a markedly raised plasma PTH of 2450 ng;l. This was interpreted as a secondary hypcr-parathyroid response to the calcitonin or an artefact. The calcitonin regimen was continued for a further 6 months when the lesion was found to be clinically and radiologically healed. Six years later she is well with no recurrence or disturbance with growth.

cuse 2 A 12-year-old boy presented with a 7-month history of mandibular swelling which had become worse during the previous 3 weeks. Clinically and radiologically there was a

large expansile cystic lesion of the mandible from the right molar region to the left premolar region (Figs IA-C). The alveolar surface was cxpandcd, smooth and rubbery and the teeth mobile. The biopsy was confirmed a central giant cell granuloma with ancurysmal bone cyst formation. (Fig. 2). His serum chemistry showed Ca 2.42 mmolil, phosphate I .24 mmol/l alkaline phosphatase 234 iu/l: albumin 45 g/l, iPTH I48 ngil. He was treated with 0.5 mg (100 units) of synthetic human calcitonin S.C. daily. After 3 weeks treatment, the teeth were noticeably firmer and at 6 months the swelling appeared to bc reduced. A second biopsy still showed a giant cell granuloma with microcyst formation. After 14 months of calcitonin therapy there was no detectable deformity clinically and radiographically and a subsequent biopsy showed normal bone. The calcitonin was stopped. Five years later he is well without deformity (Fig. ID).

Case 3 A l4-year-old Greek boy presented with a swelling of the left face which had been present for 4 years. He had undcrgonc two previous operations to reduce the enlargement and had lost his left maxillary dentition and alveolus. He now had complete obstruction of the left nasal airway

Fig. 1 -Case 2. Expansion of the mandible extending from the right second (C) radiographically (D) the patient 4 years later showing normal growth.

molar

to the left second

premolar

seen (A) clinically,

(B) and

Central giant cell granulomas of the jaws regress with calcitonin therapy mcnt he shows no sign of recurrence growth (Fig. 3E).

.or disturbance

91 in

Cuse 4

Fig. 2 - Case 2. Granuloma showing multinucleate giant cells with coalcsccnt spindle cells and cystic areas characteristic of the aneurysmal bone cyst.

and elevation of the left eye with tclccanthus (Fig. 3A). A CT scan confirmed a mixed soft and hard tissue density filling the left maxilla. nasal airway and cthmoid air cells with substantial bone destruction (Fig. 3R). His serum chemistry (1 l/l l/87) was normal for his age (Table). Giant cell granuloma had been confirmed histologically, but in view of the extensive and aggressive nature of the lesion, a maxillectomy had been proposed. After 6 months of daily human synthetic calcitonin 0.5 trig (100 iu) S.C. there was littlc perceptible change. His calcium chemistry remained normal (12/4/88). When reviewed 6 months lal.er an improved airway was noted and the nasal swelling exhibited elastic compressibility. Exploration under general anacsthctic released scrosanguineous fluid scqucstered in an enlarged antral cavity which extended into tkc ethmoidal region. The granuloma appeared to have regrc:ssed leaving encysted fluid. Drainage was established by an inferior turbincctomy. Calcitonin was stopped after I4 months (2/l/89). At I8 months (30:‘4/89) his facial appearance was normal and the CT scan conSrmcd excellent remodelling of the maxilla and orbital floor (Figs. 3C & D). However a rcvicw scan at 27 months suggested a recurrence within the antrum which was confirmed by biopsy. This remitted with a further 6 months treatment consisting of 4 daily injections 0.5 mg subcutaneously of human calcitonin and 3 days treatment with a salmon calcitonin inhaler 200 iu in the left nostril, each week. Five years after commencing treat-

A 59-year-old lady presented with a fleshy swelling in the lower left molar region of 5 weeks duration. It was removed by excision and curettage to its bony base. Histology was a peripheral giant cell granuloma and hyperparathyroidism was excluded by calcium chemistry. Ca 2.37 mmolil, phosphate 1.13 mmolil, albumin 42 g/l, alkaline phosphates 77 iuJ. Two months later it recurred and was m-excised. Three months later it recurred again. The calcium chemistry was repeated and was normal except that the iPTH < 125 mg:‘l was described as being surprisingly low, but probably an artefact. After the second recurrence it was decided to start calcitonin treatment with 0.5 mg (100 iu) synthetic salmon calcitonin, s.c.:‘daily. The mass shrunk and was firmer, but after 6 months the patient complained of weight gain and flushing and was changed to human calcitonin for a further 4 months. Unfortunately her husband had suffered a myocardial infarct and so fell out of review for I4 months. The lesion was then found to have shrunk and was excised 2 years after initial presentation with no further rccurrcnce. Her calcium chemistry remained normal Ca 2.37 mmol!l: phosphatc 0.91 mmol!l, albumin 42 g/l, alkaline phosphatase 79 iu/l.

DISCUSSION Calcitonin had no discernible immediate or long-term side effects in these three children nor in three other

patients reported to the author. In another child treated clscwhere the injections were stopped because she complained of nausea. It may bc possible to substitute the salmon calcitonin nasal inhaler (200 i.u.) for the subcuatenous injections, but this was only tried for a short period with one patient. However, the case for hormonal control of idiopathic central lesions is well made by the three described patients, in particular the third, who had already undergone unsuccessful surgery on two occasions with recurrences and extension of the lesion. He was referred for a maxillectomy. The second patient had

Table-Case 3. There was no detectable abnormality in the calcium chemistry prior, during or after treatment with calcitonin. The high alkaline phosphatasc levels are normal for the patient’s age

Date

Calcium (2.15-2.55) m.mols;l

Phosphate (0.8-I .4) m.molsJ

Albumin 35-51 g:1

Alkaline phosphatasc iu*

11:11:87 12:‘4:88 27/4:88 lo;8~88

2.35 2.54 2.48 2.35

1.4 1.O3 1.74 1.38

46 49 46 46

215 210 304 180

2/l/89 10:4:89 6:‘1I:89 17:2:90 17:9;90 26:‘8/9 1

2.22 2.32 2.37 2.34 2.35 2.22

1.35 I.35 I .2s 1.21 1.00 I .22

47 45 47 42

205 193 148 174 343 I24

*All normal for age.

49

PTH (C terminal. O-l ng:ml) 0.39 (intact mol. (8. -55 p&ml) 17.6 17.3 36.4 14.9 I6 34.8

Calcitonin r&ml* 2.2

18.1 17.8

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Fig. 3 - (A) Case 3 shows maxillary

mass elevating left globe with teldPmRus; (B) CT scan showing mixed soft and calcifrcd tissue mass filling the left antrum and nasal airway; (C)Three dimensional CT reconstruction showing destruction of left maxilla. orbital floor and ethmoid air cells; (D) Remodclling of maxilla and orbital floor 18 months after commencement of treatment; (E) Two years after completion of treatment showing normal facial contour and growth.

the features of an aneurysmal bone cyst which may be considered to be an aggressive cystic giant cell granuloma. Although curettage is recommended for such cases, rccurrencc is often rapid and dramatic, hence the practice to resect aneurysmal bone cysts of the jaws extraperiosteally or irradiate the lesion and risk malignancy in later life. Figure 4 shows an aneurysmal bone cystic form of a giant cell granuloma in the right maxilla of a 12-year-old. This was treated by extensive curettage on two occasions, following

which a further recurrence necessitated a maxillectomy. By contrast an additional patient (not described above) also presented with a recurrent giant cell tumour of the mandible which continued to extend despite calcitonin therapy. A subsequent re-biopsy of this lesion ultimately revealed an osteosarcoma which was treated by chemotherapy and resection. The recurrent peripheral giant cell granuloma rcspondcd to calcitonin by shrinking and losing its vascular fleshy consistency but the resultant fibrous

Central

giant

cell granulomas

of the jaws

regress

with

calcitonin

Fig. 4 - This patient shon.5 the natural surgical history of the giant cell granuloma with aneurysmal bone cyst changes. left eye and expansion of the maxilla; (B) Radiograph showing the characteristic semi-radiolucent blowout appearance. were taken after the first extensive curcttaw and before a further attempt lo remove the lesion by curettage. (C) shows (D) shows the patient 7 years later, follow& maxillcctomy.

cpulis did not melt away. Therefore calcitonin would appear to be useful in conjunction with excision for aggrcsive peripheral lesions. For many years kistopathologists have sought to differentiate the giant cells in bony lesions from osteoclasts. The spirdle cells have usually been considered to be osteoprogenitor cells, i.e. osteoblast precursors (Everso 8: Rovin, 1972). Flanagan et al. (1989) took fresh biopsy tissue of the first 2 cases together with six peripheral granulomas and established that the giant cells were osteoclasts on the basis that: (a) They excavated bone in vitro. (b) They show characteristic behavioural and morphological changes in vitro in response to calcitonin. (c) Ostcoclast specific monoclonal antibodies bind to

therapy

93

(A) Elevation of the Both (A) and (B) second recurrence.

them, but not to macrophages or multinucleate macrophage giant cells. They also shared these characteristics with the giant cells of the giant cell tumour. Whereas the osteoblast is of mesenchymal origin, the osteoclast is now considered to bc a haematogenous macrophage-like cell arising either from a resting precursor in the marrow or bloodstream. Despite this the recruitment and activation of the ostcoclast is stimulated by the osteoblast (Chambers, 1985) which is now known to possess the parathyroid hormone receptor. However, the controlling intercellular messenger(s) has not yet been identified. This implies that the fundamental disturbance in those lesions affects the osteoblast or its progenitor spindle cell and the aggressive foci of osteoclasts arc merely a secondary epiphcnomenon (Fig. 5). Why a year’s treatment of

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Surgery the Division of Endocrinology. the Alexander Hospital. Athens and Dr Anna Patrikiou for supervising the treatment of the third patient. and MS Yvonnc Shirley who typed the manuscript.

Osteoblast

PTH

,,.,.

“‘..,,. --.

-\

Osteoclast

References

PTHrp?

Growth Hormone? Somatomedins?

Fig. 5 - Normally the osteoclast is recruited and activated by ostcoblasts in response to parathyroid hormone. cicosanoids and cytokines (open arrows). The spindle cells may be abnormal osteoprogenitor cells releasing excess osteoclast activating cytokines (closed arrows).

the pubertal central lesion with calcitonin has proved therapeutic is not clear. It suggests a successful inhibiting function during a transient period of hormonal disturbance. The primary stimulus does not appear to be raised parathyroid hormone which was initially normal in all cases. It could however be a parathyroid hormone related peptide (PTHrP) not detected by the immune assay, but the source of this cytokine and why it provokes a localiscd lesion remains unanswered. Davis et al. (1991) cited a case of multifocal recurrent giant cell lesions one of which involved the maxilla, with a raised PTHrP. However, the patient was post pubertal (aged 26 years) and with persistent lesions after diphosphonate therapy, all of which suggest a latent PTHrP secreting neoplasm. Although oral diphosphonate is a more convenient therapy, its action is the non specific arrest of bone formation and resorption and would result in rickets after 3 months therapy in growing children. The occurrence of central lesions of the jaws in early puberty suggest an interaction of systemic or local tissue growth factors and some dental change such as tooth development and/or eruption. The nature of this problem remains to be revealed. Acknowledgments I am very grateful to Dr John Stevenson course of human calcitonin. to Professor

Bernier, J. L. & Cahn, L. R. (1954). The peripheral giant cell reparative granuloma. Juurnd ofrhe American Denral Association, 49, 141. Chambers, T. J. (1985). The pathobiology of the osteoclast. Journal of Clinical Puthology, 38. 24 I. Davis, J. P., Archer? D. J., Fisher. C.. Winalawansa. S. J. & Baldwin, D. (1991). Multiple recurrent giant cell lesions associated with high circulating levels of parathyroid hormone-related peptide in a young adult. Brirish Journul of Oral und Maxillofarial Surgery, 29. 102. Deeb, M. E., Sedano. H. 0. & Waite, D. E. (1980). Ancurysmal bone cyst of the jaws. Report of a cast associated with fibrous dysplasia and rcvicw of the literature. Infernarional Journal of Oral Surgery, 9,301. Eversole. L. R. & Rovin, S. (1972). Reactive lesions of the gingiva. Journal of Oral Parhologyj 1.30. Flanagan, A. M., Tinkler. S. M. B., IIorton. M. A.. Williams, D. M. &Chambers: T. J. (1989). The multinucleate cells in giant cell granulomas of the jaw arc ostcoclasts. Cancer, 62, 1139. Jaffe, H. L. (1953). Giant cell reparative granuloma, traumatic bone cyst and fibrous (libro-osseous) dysplasia ofjaw bones. Ord Surgery, Oral Medicine. Oral Pathology, 6, 159. Katsikeris, N.. Kakarantzi-Angelopoulou. E. & Angclopoulos. A. P. (1988). Peripheral giant cell granuloma. Clinicopathologic study of 224 new cases and rcvicw of 956 reported cases. Inrerndonai Journd of Oral und Muxillofaciul Surgery, 17,94. Saltzman, E. I. & Jun: M. Y. (1981). Ancurysmal bone cyst of the mandible. Report of a case. Jownd of Surgical Oncology, 19, 385. Walden, C. A. & Shafer, W. G. (1966). The central giant cell reparative granuloma of the jaws: An analysis of 38 cases. American Journal of Clinicd Purhology, 45, 437.

The Author 41. Harris MD, FDSRCS, FFDRCSI Professor of Oral and Maxillofacial Surgery Joint Department of Maxillofacial Surgery and Oral Medicine The Eastman Dental and University College Hospitals 256 Gray’s Inn Road London WCIX 8LD Correspondence

for providing P Papapetrou.

the first Head of

and requests

Paper received I June 1992 Accepted I4 September 1992

for offprints

to Professor

M. Harris