Biologic variations in giant-cell lesions of the mouth

Biologic variations in giant-cell lesions of the mouth Sol Silverman, Jr., MA., D.D.S., William H. Ware, D.D.S., M.D.S., and Louis T. Dimas, D.D.S., San Francisco, Calif. SCHOOL

OF DENTISTRY,

UNIVERSITY

OF

CALIFORNIA

T

issue specimens from various oral lesions occasionally contain giant cells. The origin, identification, behavior, and response to treatment of these lesions have been controversial subjects, creating much confusion among clinicians in the management of patients. Therefore, in this article we will discuss some biologic variations of giant-cell lesions of the mouth and illustrate problems in diagnosis and treatment by presentin,0 a group of casesof histologically classified giant-cell lesions. HISTORY

Cooper,‘2 in 1818, was the first to present a gross description of tumors that may have been associated with giant cells. In 1845 Lebertl” published the first microscopic description of giant cells occurring in these tumors; he referred to them as ‘ ‘ mother cells. ’ ’ RobinZg in 1849, described the giant cells occurring in certain tumors in more detail and referred to them as “plaques with multiple nuclei. ” Paget, in 1854, suggested the term myeloid for this tumor, assuming that these multinucleat,ed cells that characterized the tumor were the same cells as those found in young bone marrow. Nelaton,27 in his monograph published in 1860, was the first to state that a precise diagnosis and treatment plan are impossible without a microscopic analysis and that the prognosis is dependent upon complete excision and cauterization. He also made the first attempt to grade the tumors on the basis of his microscopic findings. In 1864, Virchow3” pointed out that multinucleated cells were also to be found in pathologic tissues not associated with bone and that, therefore, it was neither accurate nor proper to name these tumors as myeloid; instead, he introduced the term giant-cell tumor. Bloodgood, in 1912, emphasized the benign characteristics that may ac346

Volume Number

18 3

Giant-cell

lesions of mouth

347

company these lesions and urged the usage of giant-cell tumor instead of giantcell sarcoma. He cited several cases in which curettage led to complete cure. Many early reports attempted to explain the basic nature of these lesions. Mallory,23 in 1911, viewed the presence of giant cells as a foreign-body reaction in an area of retrograde change. Barrie” and Lubarsehz2 considered these lesions as posthemorrhagic reparative granulomas. KonjetznylS experimentally demonstrated intramedullary hemorrhage which caused a reactive proliferative process similar to that found in giant-cell lesions. Ewing,13 in 1922, Bloodgood, in 1923, and Geschickter and Copeland,lj in 1930, considered these lesions to be neoplastic. In 1940 ,Jaffe, Lichtenstein, and Portisl’ attempted to clarify some of the confusion by defining and grading true giant-cell tumors of bone and separating them from reparative granulomas. They also differentiated these neoplastic and inflammatory processes from other lesions which may contain giant cells, such as nonosteogenic fibroma of bone, fibrous dysplasia, chondroblastoma, chondromyxoid fibroma of bone, and the brown tumors of hyperparathyroidism. INTRAOSSEOUS JAW LESIONS Jaff e,16 Thoma,35 and Bernier and Cahn4 consider the giant-cell lesions of the jaws to be two separate entities-one a giant-cell reparative granuloma and the other a true giant-cell tumor. The latter, they believe, is a counterpart of the lesion found in long bones with a specific and usually aggressive clinical nature. LichtensteinzO interprets the true giant-cell tumor of bone as a distinctive neoplasm apparentIy arising from the nonbone-forming supporting connective tissue of the marrow. In 1953 Wa1dron37 microscopically reviewed twenty-eight lesions reported as central giant-cell tumors of the jaws. He reflected the confusion in classification by pointing out that he thought only five of these lesions appeared ident.ical to the neoplastic giant-cell tumor of bone associated with recurrences and clinical aggressiveness.It must be remembered, however, that only a small number of giant-cell tumors of long bone are malignant.2G Jaffe,16 as recently as 1953, stated that he had seen only one authentic case of true giant-cell tumor of the mouth. In 1959 Bhaskar, Bernier, and Godby surveyed the records and histologic slides of 104 giant-cell lesions of the jaws on file at the Armed Forces Institute of Pathology. They interpreted all these as reparative granulomas, with the exception of several cases of aneurysmal bone cysts, and concluded that the true giant-cell tumor of bone has no counterpart in the jaws. Austin, Dahlin, and Royer, in 1959,’ report.ed on sixty-six cases of central giant-cell lesions of the jaws seen at the Mayo Clinic during a 52 year period. They classified sixty-four as reparative granulomas and two as genuine giantcell tumors of bone. Shklar and Meyer,31 in a review of giant-cell lesions illustrated with ten case reports, conclude that, microscopically, many of these lesions fulfill the criteria of bona fide tumors. They believe that clinical and roentgenographic findings must be correlated with the microscopic data before one can fully understand the histogenesis and attempt treatment. Exactness in differentiating

348

Nilvcr?ncln

rt cd.

O.S., 0.x & 0.1’. sc.pmt,er, 196‘4

a tumor of Ilyperparath~roidislrl from the true giant-w11 tumor as n-cl1 as drawing a definitive line between a trnc giant-cell tumor and a giant-cell reparativtr granuloma was questioned. Some diagnostic limitations of depending solely upon histologic morphology are well illustrated by several al.Iicles 8%!)s24.:34in a rpce*lt supplement to ORAL SURGERT, ORAL NHDICINE:, ORAL PATTIOLOGY dealing IINI) with cherubism and other intraosseous giant-cell lesions. Uuring the past dccadc thew ha~c been many casfl report,s of giant-cell lesions, but they have srrwd only to further document, the occurrence of’ thrst lesions and re-emphasize the enigma. that still surrounds the classification and biology of giant-cell lesions. EXTRAOSSEOUS

JAW

LESIONS

The extraosseous giant-cell lesion is thought to be the peripheral eounterpart of the intraosscous giant-ccl1 reparative granuloma.“, lG,20,35 It is generally considered to be a reparative inflammatory process resulting from trauma rather than a lesion of neoplastic origin. Iiichtenstein *I further differentiates between the peripheral giant-cell reparative granuloma and the giant-cell epulis. He believes that the cpulis may be a complement of the intraosseous giant-cell tumor, histologically, ewn to the extent of mitotic figures in the stromal cells. After reviewing an txtcnsire series, CookeI1 believed the lesion to be caused by the formation of excessive and aberrant osteogenic granulation tissue. Bernie? states that an initial hemorrhage occurs as a result of trauma and that this is followed by a fibroendothelial response with an excessive production of giant cells. Jaffe and co-workers17 regard epulides as constituting a mixed group of lesions with a raried genesis which is reflected in their microscopic appearances. Possibly a lesion could develop in connection w&h local resorption of the periosteal bone of the jaw or from the undifferent,iated connective tissue of the periosteum to represent the periosteal count.erpart, of the giant-cell tumor of bone. HYPERPARATHYROID

LESIONS

Since the brown tumors of hypcrparathyroidism may sometimes he confused with other giant-cell lesions of the jawbones, the clinician must be aware of these tumors in making a differential diagnosis. These intraosseous tumors reflect part of the bone involvement of advance llpperparathyroidism.3” The lesions of primary and secondary hyperparathyroid bone disease are indistinguishable from each other. The brown tumors are not neoplasms, as shown by their spontaneous remineralization after the parathyroid adenoma is removed and the blood chemistry is corrected.“” Brown tumors probably result from direct action of parathyroid hormone on bone,14with subsequent resorption and scarring of bone and organizat,ion of hemorrhage. FUNCTION

AND

ORIGIN

The function of giant cells is not clear. Most authors have believed that they are phagocytcs. Sonic, however, hare speculated that they are osteoclasts, thus suggesting the name osteoclastoma. As for their origin, it has been postulated that they stem from megakarga.

Volume Number

Giant-cell

18 3

lesions of mouth

349

cytcs or that possibly they represent a fusion of wandering phagocytes.

Others have regarded the giant cells as having arisen from stromal cells ; and Morton,2” in 1956, upon growing giant-cell tumors in tissue culture, indicated the giant cells appeared to form from a fusion of stromal cells. This observation was also recently reported by McClendon and associates24following an explant from a giant-cell tumor. It should be pointed out, however, that cells in cultures from tissue not associated with lesions of the giant-cell type also may display this phenomenon; therefore, one should be cautious about drawing definite conclusions from this type of biologic model system. CASE

REPORTS

The following seven cases of giant-cell lesions of the mouth and jaws from the University of California Medical Center have been selected to illustrate the variabilities in clinical appearance, activity, and microscopic characteristics that make these lesions so controversial. CASE

1

A 17.year-old white schoolgirl was caused by a slowly progressive swelling

Fig. 1. A, Ocelusal roentgenogram expansion and demineralization B, Postirradiation roentgenogram size of the lesion and remineralization. ing

of

first of

seen in the left

July, 1957, because of anterior maxilla (Fig.

facial asymmetry 1, A), extending

taken in September! 1959, prior to irradiation, illustratleft anterior maxdla from a giant-cell lesion. of same patient in March, 1961, showing reduction in

Pig. 8. A, Photomicrograph of tissue specimen from giant-cell lesion shown in Fig. 1, A, displaying irregularly scattered osseous spicules found in small islets with thin trabeculae. Note that the giant cells are The fibrous connective tissue is quite cellular and compact. scarce and irregularly scattered. (Magnification, xl00 ; reduced 4s.) 23, Higher magnification of this lesion reveals an area of less cellular connective tissue stroma (a) and areas of hemorrhage (arrows) with associated giant cells. (Magnification, x150; reduced 14.)

Volume Number CASE

Giant-cell

18 3

lesions of mouth

351

2

A lo-year-old white boy was struck on the left maxilla in November, 1960. A bluish swelling in the area remained and enlarged progressively until the left hard palate expanded about 1 cm. in a firm, sessile mass (Fig. 3, A). Preoperative radiographs (Fig. 3, B) showed extensive decalcification of the left maxilla with evidence of a mass within the antrum. Root resorption of the maxillary left central and lateral incisors was also noted. In March, 1961, the patient underwent a left maxillectomy after a frozen section indicated a central giant-cell reparative granuloma. The patient recovered uneventfully, and there has been no evidence of recurrence. A review of the slide (Fig. 4, B and R) confirms the original diagnosis; this, in retrospect, raises the question of the possibility that a more conservative procedure could have been performed on this child. Fig.

3.

Fig. 4. Fig. 3. A, Photograph of a giant-cell reparative granuloma involving the left maxilla and expanding the hard palate past the midline and to the border of the soft palate. B, Roentgenogram of the same mass showing extent of bone and tooth destruction. Fig. 4. A, Low-power photomicrograph of the lesion shown in Fig. 3 demonstrates a stroma in which there are broad bands of fibroblasts that are not interspersed with any giant cells. (Magnification, x50 ; reduced I/S.) B, Higher-power photomicrograph of area a shows giant cells which are scattered in a compact fibroendothelial stroma. This isolated area resembles a true giant-cell tumor. (Magnification, x125; reduced 35.)

Pig. 5. A, Lnt.raoral radiograph taken (luring routine rsanlination of an asymptomatic patient reveals an intraosseous lc%ion. B, Photograph of t,his area stlo\ving tIlf* overlying mu~oha (arro\~ ) to ho normal in appearance. C, Photomicrograph of a specimen from this lesion showing a fibroendothelial stroma with giant cells which are small and associated with vasc~~lar channels and hemorrhage. (Magnification x150 ; reduced ?,$. ) CASE

3

During a routine oral examination of a G-year-old white woman in May, 1958, an asymptomatic intraosseous lesion of the anterior mandible (Fig. 5, il) Ivas noted. The mucosa overlying the area was normal in appearance (Fig. 5, B). A biopsy specimen was diagnosed as a ccnt,ral giant-cell reparative granuloma (Fig. 5, C). The area was thoroughly euretted and healed uneventfully without any subsequent evidence of recurrence. CASE

4

Tn April, 1960, an ll-year-old white boy lost a deciduous right maxillary cuspid. Approximately 5 weeks later a 2 by 3 em. exophytic growth (Fig. 6, A ) was noted in this area and was reported to be rapidly increasing in size. Intraoral radiographs (Fig. 6, R) showed an uneruptrd permanent. cuspid lying superior t.0 the lesion. Exfoliative I~y~oiogic study revealed no malignant cells. A Iliopsy syec:imcn was obtainc>tl, and the lesion was diagnosed as a giantj-cc~ll rpulia. Because some of these Irwions have r~pondrd to irradiation,lll and I~ausr Jurgical intc~rrention would necessitate rc~~oval of several teeth, t.he gro\vt.h was treated 11y irratliation. A total of 1,500 r was given over a 11 day period. The tumor rcgressetl in size and assumed an involuted appearance (Fig. 6, C). Four months later, however, the lesion showrd signs of renewed rapid growth. Because of its aggressive character, the tumor was exrised in November, 1960 (Fig. 6, D). Healing was

Volume ITumber

P’

18 3

Giant-cell

lesions of mouth

353

8. 6. il, Lesion of right maxilla following wnwval of a dwidunus cuspid 5 USlY. Roentgenogram of same area showing the. cuspid in pre-eruptive positicm. Appearance of the area folbx~ing jrradiation (1,500 r in 2 \veeks). Surgical specimen of right maxilla 4 months after radiation theTapy. Photomicrograph of a histologic area which gives the appearance of a true gia .&cell from the aspect of the compact and cellular stroma and distribution of giant : cells. Lany giant cells appeared to he within vascular channels (arrows). (Magnification, x125 ; :duee d 3%)

354

Hilcemlcl~ll

ct

(Il.

O.S., 0.x September,

& 0.1’. 1964

uneventful, and there has been no evidenc.ca of r~urren~(~ t.o 1 II<& pr(~sent timra. The surgical specimen (Fig. 6, B) was similar to thr! original biopsy sl~c~in~n and was tliagnoscd as a giant-ccl1 epulis. In morphology a.nd activity this lesion has many similaritic>s to the introosseous giant-cell tumor. All other clinical and laboratory studies, including strum calcium, wtm’ within normal limits. CASE

5

A 55year-old white man noticed a lesion on the lingual marginal gingiva of the maxillary right central incisor a month before seeking professional attention in February, 1960. Clinically, the lesion appeared to be granulomatous, with a tendency to bleed easily. Roentgenograms showed no bone involvement. A cytologic smear of this 3 by 5 mm. lesion was taken to

7. 8, Photomicrograph showing a giant-ceil lesion of the maxillary lingual gingiva is surrounded by a zone of fibrous connective tissue. (Magnification, x50; reduced l/5.) cellular stroma containing many B, Higher-power photomicrograph shows a compact, evenly distributed giant cells with markedly hypcrehromatic nuclei. (Magnification, x125; reduced $4.) Fig.

which

Volume Number

Giant-cell

18 3

lesions of mouth

355

any malignanthelp determine the type and extent of biopsy. 32 The smear did not reveal appearing cells. Therefore, a conservative excisional biopsy was performed and a microscopic diagnosis of peripheral giant-cell reparative granuloma was made (Fig. 7, A and B). The lesion extended down to the periosteum. Specific areas of this tissue resembled a giant-cell epulis with respect to observed mitotic figures. The area healed uneventfully, with no recurrence to date. CASE

A removal

6

33.year-old white of an osteolytic

woman lesion

in

underwent the body

a surgical procedure of the left mandible

in F ebruary, (Fig , 8, A)

1961, which

for was

Fig. 8. A, Preo] perative roentgenogram of a brown tumor located i n t:he mandible, o riginal ly diagnosed as a central giant-cell tumor. B, Photomicrogl raph of one area of specimen shown in 8, showing c one :entrations of g giant cell s in areas of he] morrhage. (Magnification, x50; reduced I$.) C, Higher-power . photomicrograph of specimen shown in B. Note gia .nt cells, unifol rmly size !d spindle-shaped stromal cells that are abundant but not densely pat :kel 3, and extravas ated red blood cells. (ME tgnification, x275; reduced I$.)

firs1 tory

noticed becaust: of jaw pain. The 1e~t1 \\:Is rcl~ntetl as a giant~l,r!ll 1urnor. l,:tlWratc’sts prompted i)y the tumor revealed ii h~l~l!‘.~~~lccl,li:~. ‘I‘hi;; lmi Lo furf.l~r-I. c~xrruiuati~~ris whiclt established a tlixgnosis of prinlar~* l~~~~~~r~~:~~~thy~oi~lisirl. This cli:tgnosis \vi~s surgic:Lll,v itnc1 microscopically proved in May, 1961, will1 the ~:WIOV-:I~ 111 Kec+overv was unevent,ful, and the hlOO~l vllc’rllist”y wiurllc~ll to llo,lllal. I’rcwl of t II<’ association of thtr jaw lesion with lI~l)(~~I~:lr:~thyruitl liolrc~ (Ii3QSc 1~x4 ~~rwludcvl by I tI(a Tht~refore, the relationship betwec~u f 11~ jaw tumol complete curettage at the original biopsy. and parathyroid activit,y in this particular V:N: can only be speculated. ‘l’tlr patient had a normal alkaline phosphatase, and thelo was no other roentgrnographic wichcx: of pxa2,

thyroid

bone

Microscopically CASE

,':I

~ittll,~~Oitl

ill~L.

disease.

(Fig.

8, B and

C),

this

tissue

was

consist~ent

with

a bro\vn

tumor.

7

A

32.year-old white woman underwent a left nephrectomy for removal of a tuberculous kidney in 1950. In 1956 an infection developed in the right kidney, with subsequent alterations in chemistry, leading to osteomalacia, osteoporosis, fractures, and bone lesions consistent with secondary hyperpamthyroidism. 1958, because of swelling and pain in the left The patient was hospitalized in June, mandible. Intraoral radiographs (Fig, 9, A) showed changes consistent with hyperparathyroid bone disease. Curettage of the radioIucent lesion and ext.raction of the involved teeth were performed. The lesion was initially reported as a central giant-cell tumor. A review of the slide (Fig. 9, B) did not support the diagnosis of a giant-cell tumor, however, because of (1) the fibrous character of the stroma, (2) the erratic distribution of giant cells and their concentration around areas of blood extravasation, and (3) the presence of immature trabecular bone. This, along with the clinical pattern, prompted reinterpretation of the lesion as a brown tumor. 1958, with a complaint of swelling and pain The patient was seen again in August, of the right anterior maxilla (l?ig. 10, A and B). Surgical intervention was not advised because of the extent of the lesion and the patient’s poor physica condition. Ionizing x-irradiation (2,850 r in 27 days) \vas administered. Tumor growth was arrested, and remineralization took place (Fig. 10, C and U), During this period the patient was also on calcium and vitamin D therapy. So further change in the patient’s oral status or general systemic condition has been noticed to the present time.

DISCUSSION AND SUMMARY The presence of giant cells in a tissue specimen assumes significance because of the difficulty in differentiating a neoplastic process, with its potential for aggressiveness and recurrence, from inflammatory processes that may not possess these properties. Alterations in density and morphology of stromal cells, number and distribution of giant cells, bone formation or destruction, and vascularity and hemorrhage characterize criteria described for classifying giant-cell lesions. The differential diagnosis may include many lesions, such as giant-cell tumor, giant-cell reparative granuloma, fibrous dysplasia, cherubism, nonosteogenic fibroma of bone and the brown tumor of hyperparathyroidism. However, the microscopic appearance of these lesions of different origin and behavior is not always characteristic enough to establish a diagnosis with sufficient certainty. Although classifications and grading have been set forth,20 the criteria as related to jaw lesions are disputed. Therefore, these lesions remain confusing and controversial. As illustrated by the cases reported here, it is not always possible to correlate and reconcile clinical appearance and behavior with microscopic features. This, then, creates a problem in planning treatment

Volume Number

18 3

‘ig.

B&J. 9. A, Roentgenogram of a mandibular lesion which was accompanied with sivelling, pain, and mobility of teeth in a patient with secondary hyperparathyroidism. Note absences of lamina dura, root resorption, and marked demineralization. B, Photomicrograph of the mandibular lesion shown in A, revealing a fibrous replacement of bone with areas of new bone formation (arrows,). The giant cells are numerous and located around vascular channels. (Magnification, x120 ; reduced 1/3. j Fig. 10. A and B, Photographs of the swelling of the right anterior maxilla of the hyperparathyroid patient shown in Fig. 9. C, Roentgenogram of this patient showing an osteolytic area which extended past the midline of the hard palate with erosion of the central and lateral incisor roots. D, Roentgenogram of the same patient 10 months after radiation therapy of the lesion, showing arrested destructive activity and remineralization.

I

IVhClY!

PstWIlGi

i'lvnl

(WlTt ilgO

I.0

cslc:nsivc

cxc%ioir

01’ irr;ldiz\lioll

lrlrlsl,

I)(:

corisidrrc~d.

\Vhiltr radiation in c(JPtilill insti~~~(~t~s III~,!- bc cwr;rti\e, its cf?wti~wctss (‘it11not 1~~ predicted. 01~ occasion silrcolll>\s have occurred iIt sites ol’ giant-cell lesions treated by radiation.:+o One surh case involved a ‘J-year-old boy given radiation treatment, for a giant-ccl1 rr])ilrative granuloma of the: lrft maxilla. Seven years later an osteogenic sarcoma was diagnosed in the samt: arcil. Whether or not this was radiation induced is yacstionable. In thctir report on rocntgenotherapy of benign giant-cell tumors of bone, Buschke and Cantril”’ cite two cases of benign giant-cell tumor of the mandible that remineralizcd following t,hcrapy. Eighteen years later one paGent dcvcloped a squamous carcinoma in the buceal mucosa adjacent to the treated mandible. Howcv.~r, the radiation dosages administered then Ivere much higher than those used today. Ruschke and Cantril cite rather rigid guidelines for contemplating radiation of thcsc lesions and infer that radiation is sec~ond to surgical management as the treatment of choice. The advantage of radiation is that it permits preservation of normal structures. However, curettage or conservati\-c excision rarely results in a permanently large defect,, and either of these surgical procedures appears to be the t.reatmerit of choiec. Giant-cell lesions associated with disorders of calcium metabolism should be treated only after the metabolic lesion is resolved. It is infrequent that the brown tumor of hpperparathyroidism requires surgical intervention after the patient’s blood chemistry has returned to normal. Because of the many reports of giant-cell lesions in the mouth being associated with hyperparathyroid disease, it is advisable to obtain a serum calcium determination in view of the fact that hypercalcemia is the most consistent finding in hyperparathyroidism.3” Because a giant-cell lesion may reflect a local neoplasia, an inflammatory process, or a parathyroid adenoma, correlation of t,he microscopic, clinical, roentgenographic, and laboratory findings is necessary before one can arrive at a definitive diagnosis and treatment plan. The seven cases presented here demonstrate the confusing biologic variations in etiology, morphology, and behavior of giant-cell lesions of the jaws. REFERENCES

1. Austin, L. T., J!.,. Dahlin, I). C., and Royer, R. Q.: Giant-Cell Reparative Granuloma and Related Conditions Affecting the Jawbones, ORAT> SURG., ORAI, MED. & ORAL PATII. 12: 1285-1295, 1959. 2. Barrie, G.: Multiple Hemorrhagic Foci in Bone, Ann. Hurg. 71: 581-593, 1920. 3. Bernier, J. L.: The Management of Oral Disease, ed. 2, St. Louis, 1959, The C. V. Mosby Company, pp. 638-642. 4. Bernier, J. L., and Cahn, L. R.: The Peripheral Giant, Ccl1 Reparative Granuloma, J. Am. Dent. A. 49: 141-148, 1954. 5. Rhaskar, S. N., Bernier, J. L., and Godby, F.: hncurysmal Bone Cyst and Other Giant Cell Lesions of the Jams: Report of 104 Cases, J. Oral Surg., Ancsth. & Hosp. D. Serv. 17: 30.41, 1959. 6. Bloodgood, J. C.: The Conservative Treatment of Giant-Ccl11 Sarcaoma, With the Study of Bone Transplantation, Ann. Surg. 56: 210-239, 1912. 7. Bloodgood, J. C.: Benign Giant Cell Tumor of Bone; Its Diagnosis and Conservative Treatment, Am. J. Surg. 37: 105-112, 1923. 8. Bloom, J., Chacker, F. M., and Thoma, K. H.: Multiple Giant-Cell Lesions of Bone, ORAL SURO., ORAL MED. & ORAL PATH. 15: Supp. 2, 1962, pp. 74-83.

Volume Number

18 3

Giant-cell

lesions of mouth

359

9. Burland, J. G.: Cherubism: Familial Bilateral Osseous Dysplasia of the Jaws, ORAL SURG., ORAL MED. & ORAL PATH. 15: Supp. 2, 1962, pp. 43-68. of Benign Giant-Cell Tumor of 10. Buschke, F., and Cantril, S. T.: Roentgentherapy Bone, Cancer 2: 293-315, 1949. 11. Cooke, B. E. D.: The Giant-Cell Epulis: Histogenesis and Natural History, Brit. D. J. 93: 13-16, 1952. 12. Cooper, A., and Travers, B.: Surgical Essays, ed. 3, London, 1818, Cox & Sons, vol. 1, pp. 186-207. 13. Ewing, J.: A Review and Classification of Bone Sarcomas, Arch. Surg. 4: 485-533, 1922. 14. Firschein, H. E., Neuman, W. F., Martin, G. R., and Mulrgan, B. J.: Studies on the Mechanism of Action of the Parathyroid Hormone, Recent Progr. Hormone Res. 15: 427-454, 1959. 15. Geschickter, D. F.. and CoDeland. M. M. : Tumors of the Giant Cell Group _ ; A Pathologic Entitv. Arch. Su&. 21: 145156.’ 1930. 16. Jaffe: ‘H. L.: G&t Cell Rep&ative Granuloma, Traumatic Bone Cyst, and Fibrous (Fibro-osseous) Dysplasia of the Jaw Bones, ORAL SURG., ORAL MED. & ORAL PATH. 6: X9-175. 1953. 17. Jaffe, I%. L. Lichtenstein, L., and Portis, R.: Giant Cell Tumor of Bone; Its Pathologic Appearance, Grading, Supposed Variants, and Treatment, Arch. Path. 30: 993-1031, 1940. 18. Konjetzny, G. E.: Die Sogennante “Lokalisierte Osteitis Fibrosa,” Arch. klin. Chir. 121: X7-634. 1922. 19. Lebert, H.: ‘Physiologic pathologique, Paris, 1845, 5. B. BailliBre, vol. 2, p. 125. 20. Lichtenstein, L.: Bone Tumors, ed. 2, St. Louis. 1959, The C. V. Mosby Company, pp. 119-145. 21. Lichtenstein, L.: Personal Communication. 22. Lubarsch, 0.: Die Sogennante “Lokalisierte Osteitis Fibrosa,” Arch. klin. Chir. 121: 147, 1922. 23. Mallory, F. B.: Giant Cell Sarcoma, J. M. Res. 24: 463-467, 1911. 24. McClendon, J. L., Anderson, D. E., and Cornelius, E. A.: Cherubism-Hereditary Fibrous Dysplasia of the Jaws. II. Pathologic Considerations, ORAL SURG., ORAL MED. & ORAL PATH. 15: Supp. 2, 1962, pp. 17-42. Morton, J. J.: Giant Cell Tumor of Bone, Cancer 9: 1012-1026,1956. 2 Murphy, W. R., and Ackerman, L. V.: Benign and Malignant Giant-Cell Tumors of Bone: A Clinical-Pathological Evaluation of 31 Cases, Cancer 9: 317-339, 1956. E. : D’une nouvelle esp&e de tumeurs benignes des OS, ou tumeurs B myhlo27. Nelaton, plaxes, Paris, 1860, Adrien Delahaye. 2s. Paget, J.: Lectures on Surgical Pathology, Philadelphia, 1854, Lindsay & Blakiston, pp. 446-447. 29. Robin, C.: On the Existence of Two Species of Anatomical Elements Which Are Located in the Medullary Canal of the Bones, Compt. rend. Sot. biol. 1: 349-150, 1849. 30. Sabanas, A. O., Dahlin, D. C., Childs, D. S., and Ivins, J. C.: Post Radiation Sarcoma of Bone, Cancer 9: 528-542, 1956. 31. Shklar, G., and Meyer, I.: Giant-Cell Tumors of the Mandible and Maxilla, ORAL SURG., ORAL MED. & ORAL PATH. 14: 809-827, 1961. Sol, Jr. : Early Detection of Oral Cancer-A Simple Screening Technic, 32. Silverman, PDM, pp. 3-31, July, 1959. 33. Silverman, S., Gordon, G., Steinbach, J., Eisenberg, E., and Manson, R.: The Dental Structures in Primary Hyperparathyroidism: Studies in 42 Consecutive Dentulous Patients, ORAL SURG., ORAL MED. & ORAL PATH. 15: 426-436, 1962. 34. Thoma, K. H.: Cherubism and Other Intraosseous Giant-Cell Lesions, ORAL SIJRO., ORAI, MED. & 011.41, PATH. 15: SUDD. 2. 1962. DD. l-4. K. H., and Goldm& g. M.:‘&al Pathology, ed. 5, St. Louis, 1960, The C. V. 35. Thoma, Mosby Company, pp. 1291-1300. 36. Virchow, R. : Die Krankhaften Geschwiilstc, Berlin, 1864, A. Hirschwald, vol. 2, pp. 209-213. 37. Waldron, C. A.: Giant Cell Tumor of the Jawhones, ORAL SIXG., ORAL Mm. & ORAL PATH. 6: 10551064, 1953.