Annals of the Rheumatic Diseases 1992; 51: 1335-1337

Giant cell tumours in mandible and spine:a rare complication of Paget's disease of bone

M Bhambhani, B G H Lamberty, M R Clements, S J Skingle, A J Crisp

AbstractThe case of a man who was diagnosed ashaving polyostotic Paget's disease at theage of 52 years is described. He developed arare neoplastic complication of Paget'sdisease a giant cell tumour in his mandible,which was excised. Nine years after thediagnosis of this tumour he developed a newgiant cell tumour arising from the L3 vertebralbody. He was born in Avellino in Italy, fromwhere five other cases of giant cell tumoursarising from Pagetic bone disease have beenreported. No family relationship between ourpatient and the other cases was established.His Paget's disease was particularly aggressiveand resistant to treatment with two single highdose infusions of pamidronate almost twoyears apart.

(Ann Rheum Dis 1992; 51: 1335-1337)

The development of malignant osteosarcoma isa well known but rare complication of Paget'sdisease,' and it is often assumed that allneoplastic transformations in Paget's disease aremalignant and universally fatal. Giant celltumour is an even rarer complication of Paget'sdisease.2

and lower jaw, and radiography showed typicalPagetic changes in the mandible. Treatmentwith etidronate 400 mg daily, calcium, andvitamin D (25 ,ug calciferol) was started. Hisserum alkaline phosphatase level before treat-ment was 1690 IU/l. After six months' treatmentthis level had fallen to 369 IU/l but with only amodest improvement in his symptoms. Withinthree weeks of stopping treatment the serumalkaline phosphatase level had risen again to1150 IU/l. A second course of etidronate wasgiven with a nadir of alkaline phosphatase of347 IU/l. He then had two courses of mithra-mycin (15 gig/kg daily for five days per course),with improvement in his symptoms, followedby combinations of treatment with etidronate400 mg daily and salcatonin 100 units daily,covered by pizotifen (1-5 mg daily) to reduceside effects.3 He was then able to toleratesalcatonin but continued to have severe lowerjaw pain. After this he developed an ulceratingmandibular swelling with loosening of the lowerfour incisors (fig 1). The mass was biopsied and

Department ofRheumatology,Addenbrooke's Hospital,Cambridge, CB2 2QQ,United KingdomM BhambhaniS J SkingleA J CrispDepartment ofPlastic Surgery,Addenbrooke's Hospital,Cambridge, CB2 2QQ,United KingdomB G H LambertyDepartment ofMedicine,Addenbrooke's Hospital,Cambridge, CB2 2QQ,United KingdomM R ClementsCorrespondence to:Dr Crisp.Accepted for publication15 July 1992

Case reportA man born in 1925 in Avellino near Naples inItaly was referred to Addenbrooke's Hospital in1980 with a three year history of widespreadPaget's disease affecting his skull, jaw, cervicaland thoracic vertebrae, ribs, femora, andproximal tibiae. He complained of generalisedmusculoskeletal pains, headaches, tinnitus, anddeafness. He had previously worked in Belgiancoalmines but was now employed as a machineoperator in England. He had had a duodenalulcer in 1962 but had otherwise been well.There was no recorded family history of Paget'sdisease or bone tumours.

Examination showed skull enlargement, adorsal kyphosis, and bilateral sensorineuraldeafness.

Investigations showed normal blood urea,creatinine, electrolytes, and glucose; serumcalcium 2-37 mmol/l (normal range 2-2-2-6),phosphate 1-22 mmol/l (0-8-1-4), and serumalkaline phosphatase 1410 IU/l (30-135). Radio-graphy showed Paget's disease in the skull vaultwith basilar invagination, in several vertebralbodies, pelvis, ribs, femora, and tibiae.He was unable to tolerate salcatonin 100 units

daily. He then complained of pain in his teethFigure I This shows a mandible expanded by the tumourmass which has ulcerated through the skin.

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Bhambhani, Lamberty, Clements, Skingle, Crnsp

then curetted in 1982. Histological examinationshowed a mass of closely packed multinucleatedgiant cells of variable size and nuclear numberconsistent with the diagnosis of benign giant celltumour (fig 2). Electron microscopy of the giantcell nuclei showed paramyxovirus-like inclusion

Figure 2 The histology ofthe giant cell tumour arisingfrom Pagetic bone. Note theconnective tissue containing a mass ofclosely packed multinucleate cells ofdifferent sizes.

Figure 3 A radiograph ofthe mandible showing lyticlesions and bony erosion.

bodies. Treatment with etidronate and salcatonincontinued with the lowest value of serumalkaline phosphatase so far achieved of 329 IU/l.About six months later a further swelling of

the mandible appeared and was again curetted.The tumour was noted to have invaded striatedmuscle. Curettage was incomplete and thetumour mass again expanded. This reduced insize with dexamethasone, but in 1983 themandible was irradiated (45 Gy in 15 fractionsover five weeks), with almost complete resolutionof the mass. About one year later the tumourrecurred. A computed tomographic scan showeddestruction of the mandible and muscle infil-tration which spread down to the thyroidcartilage without infiltrating it (fig 3). Thetumour was then excised and included the floorof the mouth, the gingival margin, and thewhole of the mandible from the second molarforwards on each side. Reconstruction wascarried out with an osteocutaneous radialforearm flap (BGHL). After this procedurethere was still a shortage of bone and a furtherfree osteocutaneous flap was subsequentlyrequired, again using skin paddle to allowfurther insertion of skin into the floor of themouth. There was no evidence of tumourrecurrence at this procedure.

Since these surgical procedures he has had notumour recurrence in the mandibular region,but in 1985 widespread musculoskeletal painarising from Pagetic disease of bone againbecame disabling. A bone scintigram showedincreased uptake in skull, spine, ribs, righthemipelvis, and left femur. The 24 hour wholebody retention of methylene diphosphonatewas considerably raised at 74% (normal <40%).4There was a poor clinical response to furthercourses of etidronate, and in 1988 he wasadmitted for a single infusion of 105 mgintravenous pamidronate (3-amino-1-hydroxy-propylidene-l,l-bisphosphonate) given over 24hours in 1 litre of 5% dextrose.5 The serumalkaline phosphatase level before treatment was1290 IU/1, but three months after this treatmentit had fallen to 64-3%, and the urine hydroxy-proline/creatinine ratio to 60%, of the valuesbefore treatment. There was considerableimprovement in skeletal pain for about one anda half years when there was symptomatic andbiochemical deterioration.He was readmitted for a second single infusion

of pamidronate 105 mg almost two years afterthe first treatment. Over the next three monthsthe impressive reduction in the hydroxyproline/creatinine ratio noted after the first treatmentwas not reproduced but serum alkaline phos-phatase fell to 570 IU/l. Nine years after thediagnosis of his mandibular giant cell tumour hedeveloped a right L4 nerve root lesion, andinvestigations disclosed a new giant cell tumourarising from the L3 vertebral body. He receiveda course of radiotherapy, which abolished hisback pain with resolution of his right L4 nerveroot lesion. Four months after radiotherapy hisback tumour recurred, but complete surgicalexcision of the tumour was technically impos-sible.

His tissue type was HLA-Al, A3, B12(Bw44), B17, Bw4, DRI, DR7.

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Giant cell tumours in mandible and spine

DiscussionGiant cell tumour complicating Paget's diseasewas first described in 1931,6 and since thenabout 55 cases have been reported.2 7-13 Itusually occurs in patients with severe Paget'sdisease and typically presents as a non-tendermass in the skull or facial bones, less commonlyin the remaining axial skeleton, and rarely inarms and legs.8 13 Symptoms arise from localtumour encroachment,8 and patients maypresent with epistaxis and nasal obstructionwith maxillary tumours.2Our patient's first giant cell tumour was

diagnosed five years after the diagnosis ofPaget's disease. In the series of Hutter et al 2 thediagnosis of giant cell tumour usually coincidedwith that of Paget's disease. Patients developingmalignant osteosarcoma typically have a longpreceding history of the disease.2

Malignant sarcomata sometimes haveabundant giant cells and can mimic giant celltumours. Sarcomata typically have more osteoidtissue among the malignant cells than giant celltumours.' Histological distinction is clearlycrucial for prognosis. The presence of virus-likeinclusions in osteoclastic nuclei in giant celltumours occurring in Paget's disease has beenpreviously reported.9 11 Although local recur-rence after treatment is common, metastasis isvery uncommon.8The treatment of giant cell tumour in Paget's

disease is often difficult. Small lesions may becuretted, but larger ones require resection.Glucocorticoids may cause some clinical andbiochemical improvement,8 and mithramycincan cause some tumour regression.8 Pearlmanand Friedman treated two patients with radio-therapy alone.'2 Our patient's mandibulartumour was cured only by excision surgery andjaw reconstruction.A particular feature of interest in our patient

is his origin from Avellino in Italy. Jacobs et aldescribed five cases of giant cell tumour inPaget's disease of bone in patients, all of whomoriginated from Avellino.8 Our patient hasrelatives in Avellino, including a doctor, but wehave been unable to establish any links betweenthe families reported by Jacobs et al and ourpatient's family. Multiple giant cell tumoursoccurring in the same patient must be exceedinglyrare, though one patient developed 27 similartumours.8

We have also reported the response of ourpatient's widespread active Paget's disease to asingle infusion of high dose pamidronate. 14 The105 mg dose we used gave good relief of Pageticpain and some lowering of the serum alkalinephosphatase level. This dose typically achievesan excellent clinical and biochemical remissionin uncomplicated Paget's disease and hasbecome our treatment of first choice.5 Ourpatient's nadir value of serum alkaline phos-phatase was 570 IU/1, indicating his relativebiochemical resistance to this regimen.

AddendumOne year after the development of the L3vertebral body giant cell tumour, a third giantcell tumour has been located in the nasal cavityinvading erythroid air cells and frontal sinuses.

We thank Mrs Carol Phillips for typing this manuscript.

1 Barry H C. Paget's disease of bone. Edinburgh and London:E & S Livingstone, 1%9: 136-77.

2 Hutter R V P, Foote F W, Frazell E L, Francis K C. Giantcell tumours complicating Paget's disease of bone. Cancer1963; 16: 1044-56.

3 Crisp A J. Pizotifen to prevent side effects of calcitonin.Lancet 1980; i: 775.

4 Fogelman I, Bessent R G, Turner J G, Citrin D L, Boyle I T,Greig W R. The use of whole body retention of 99mdiphosphonate in the diagnosis of metabolic bone disease.J Nucl Med 1978; 19: 270-5.

5 Bhambhani M, Skingle S J, Watts R A, Pountain G, CrispA J. Effect of single infusion of pamidronate on Paget'sdisease of bone. BrJ Rheumatol 1991; 30 (suppl 2): 95.

6 Hunter D, Turnbull H M. Hyperparathyroidism: generalisedosteitis fibrosa with observations upon bones, parathyroidtumours and normal parathyroid glands. BrJ Surg 1931-32;19: 203-84.

7 Goldenberg R R, Campbell C J, Bonfiglio M. Giant celltumour of bone. An analysis of 218 cases.J Bonejoint Surg[Am] 1970; 52: 619-64.

8 Jacobs T P, Michelsen J, Polay J S, D'Adamo A C, CanfieldR E. Giant cell tumour in Paget's disease of bone. Familialand geographical clustering. Cancer 1979; 44: 742-7.

9 Mirra J M, Bauer F C, Grant T T. Giant cell tumour withviral Like intranuclear inclusions associated with Paget'sdisease. Clin Orthop 1981; 158: 243-51.

10 Miller A S, Cuttino C L, Elzay R P, Levy W M, HarwickR D. Giant cell tumour of the jaw associated with Paget'sdisease of bone. Arch Otolaryngol 1974; 100: 233-6.

11 Carles D, Rivel J, Devars F, et al. Giant cell tumoursdeveloping in Paget's disease. Presentation of 2 cases withan ultrastructural study. Ann Pathol 1989; 9: 47-53.

12 Pearlnan A W, Friedman M. Radiation therapy of benigngiant cell tumour arising in Paget's disease of bone. Iso-effect recovery study. AmJ' Roentgenol 1968; 102: 645-51.

13 Levine H A, Enrile F. Giant cell tumour of patellar tendoncoincident with Paget's disease. J Bone Joint Surg [Am]1971; 53: 335-40.

14 Thiebaud D, Jaeger P, Goblet C, Jacquet A F, Burckhardt P.A single infusion of the biphosphonate AHPrB.P (APD) astreatment of Paget's disease of bone. Am J Med 1988; 85:207-12.

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