Primary malignant giant cell tumor of the mandible

Primary malignant giant cell tumor of the mandible Report of a case and review of the literature Greg A. Mintz, D.M.D., Albert M. Abrams, D.D.S., MS., Gary D. Carlsen, D.D.S., Raymond J. Melrose, D.D.S., and H. William Fister, M.D., Los Angeles, Cal$ SCHOOL

OF DENTISTRY,

UNIVERSITY

OF SOUTHERN

CALIFORNIA

The first documented case of primary malignant giant cell tumor of the jawbones is reported. The neoplasm presented as a lytic lesion of the mandible which recurred following surgery and metastasized to the lungs and one lymph node. Diagnostic criteria are discussed, and the literature concerning malignant giant cell tumors of the jawbones is reviewed.

M

alignant giant cell tumors of bone have been divided into primary and converted (or secondary)types. ’ Primary malignant giant cell tumors of bone are malignant at the time of initial presentation, while lesionsof the converted variety present initially as benign giant cell tumors and subsequentlyundergo malignant transformation. The malignant transformation of benign giant cell tumor, most often following radiation treatment but occasionally following surgery alone, hasbeen well documented in several published series of giant cell tumors.‘-” This transformation takes the form of fibrosarcoma, osteosarcoma,or giant cell tumor with malignant stromal cells.6 It must be emphasizedthat the use of the term secondary or converted malignant giant cell tumor of bone to describea sarcomaindicates only that the sarcomahas developed as the result of malignant transformation of giant cell tumor and does not indicate that the sarcoma bears a histologic resemblanceto giant cell tumor of bone. Primary malignant giant cell tumors of bone have been a much more controversial subject for several reasons. First, many authors have failed to specify the criteria used in making the diagnosis and therefore have made it impossible to compare one case report with the

next. Second, the diagnosis has been inappropriately applied to sarcomasof bone, such as osteosarcomas, which may contain numerous nucleated giant cells. ’

benign-appearing

multi-

Dahlin and his colleagues*have specified diagnostic criteria which offer some assurance that a lesion diagnosed as a malignant giant cell tumor of bone bears 164

relationship

to typical

giant cell tumor

of bone. These

authors proposedthat “to qualify as a malignant giantcell tumor, a tumor must have histologic evidence of the benign counterpart in the lesion material removed previously from

under study or in the same area. ”

With these criteria the diagnosis of primary malignant giant cell tumor of bone would be applied to any bone sarcoma which, at initial presentation, of typical benign giant cell tumor.

contained

areas

The following casereport documentsa primary malignant giant cell tumor of the mandible which meets the aforementioned criteria. CASE

REPORT

A 55-year-old white man was seen in January, 1978, with a 3-week history of painful swelling of the left mandible accompanied by paresthesia of the lower lip on the same side and headaches at night. His present illness began in August, 1977, when he developed numbness of the left lower lip. The numbness developed immediately following the surgical removal of a pilonidal cyst and was interpreted at that time to be the result of “pressure on the lip during the surgical procedure.” No further actjon was taken at that time. The patient’s medical history was unremarkable. His surgical history included the removal of a basal cell carcinoma from the back in 1977. Extraoral examination revealed a slightly tender swelling on the left side of the face (Fig. 1). Intraoral examination disclosed firm enlargement of the left body, angle, and ramus of the mandible. The overlying mucosa was intact, with no evidence of inflammation or ulceration. The remainder of the physical examination findings were unremarkable. Lateral jaw and anteroposterior radiographs (Figs. 2 and 3) revealed a 4.5 by 2.5 cm. multiloculated, relatively well-circumscribed 0030.4220/81/020164+08$00.80/0

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Fig.

1.

Frontal view of patient, showing left facial swelling.

radiolucency involving the left body and inferior portion of the ramus of the mandible. There was expansion of both buccal and lingual cortical plates, with marked thinning of the cortex at the inferior border of the mandible. The blood count and differential, prothrombin time, partial thromboplastin time, and serum calcium level were within normal limits. The alkaline phosphatase level was 73 I.U. (normal, 36 I.U. to 92 I.U.). A differential diagnosis consisting of benign tumors, with ameloblastoma being the most likely possibility, was formulated and an incisional biopsy was performed. The biopsy specimen consisted of multiple fragments of tan-brown soft tissue measuring in aggregate 3.5 by 2.5 by 0.6 cm. The specimen was processed conventionally and submitted for light microscopy. Microscopic examination revealed a moderately vascular proliferation of spindle to ovoid stromal cells interspersed with numerous benign-appearing multinucleated giant cells. In some areas the stromal cells were arranged in a whorling fashion (Fig. 4) with indistinct cell boundaries. For the most part, the nuclei of the stromal cells closely resembled the nuclei of the multinucleated giant cells, but in focal areas the stromal cells showed moderate variation in nuclear size and staining with several mitotic figures per high-power field. Because of these worrisome areas, the biopsy specimen was diagnosed as an atypical giant cell lesion and slides were sent to a variety of consultants. The diagnoses ranged from benign (giant cell granuloma) to malignant, with most consultants favoring a diagnosis of sarcoma, type not specified. Because the lesion was enlarging rapidly and because the preponderance of diagnoses favored a malignant interpretation, a decision was made to perform a wide resection. One month following initial presentation the patient underwent a left hemimandibulectomy and immediate mandibular reconstruction with a rib graft. The contents of the submandibular triangle were removed at the same time. Pathologic specimen

examination

of the hemimandibulectomy

The gross specimen consisted of a left hemimandibulectomy specimen measuring 12 cm. in length. The neoplasm

Fig. 2. Lateral jaw radiograph of left mandible demonstrating relatively well-circumscribed, multiloculated radiolucency. Note marked thinning of cortex at inferior border.

Fig. 3. Anteroposterior radiograph demonstrating of buccal and lingual cortical plates.

expansion

produced a fusiform dilatation of the mandible, and sectioning of the specimen revealed infiltration of the marrow spaces by nodular gray-white tumor. The tumor penetrated the cortex and periosteum and extended into the surrounding soft tissues, where it appeared more red-brown. Multiple sections of the tumor submitted for light microscopy revealed a neoplasm characterized chiefly by proliferation of ovid to spindle stromal cells with numerous benignappearing multinucleated giant cells. The nuclei of the stromal cells contained finely dispersed chromatin with prominent nuclear membranes and a small nucleolus. In focal areas the nuclei of the stromal cells appeared essentially identical to the nuclei of the giant cells (Fig. 5). These areas appeared typical of giant cell tumor. The predominant histologic pattern maintained the same arrangement of stromal and giant cells typical of giant cell tumor, but slight variation in nuclear size and staining combined with a high rate of mitotic activity (often two to five mitoses per high-power field) clearly

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Fig. 4. Photomicrograph of incisional biopsy specimen demonstrating whorling arrangement of stromal cells. Several benign-appearing multinucleated giant cells are interspersed among stromal cells. (Hematoxylin and eosin stain. Original magnification, X 250.)

Fig. 5. Photomicrograph of resection specimen showing proliferation of stromal and benign-appearing cleated giant cells typical of giant cell tumor. (Hematoxylin and eosin stain. Original magnification, pointed to the malignant nature of these stromal cells (Fig. 6). Other areas contained interlacing bundles of spindle cells typical of fibrosarcoma (Fig. 7). There was no evidence of osteoid or bone production by malignant stromal cells in any of the sections studied. The giant cells were numerous and showed considerable variation in size; some contained as many as 100 nuclei in a

multinu100.)

x

single plane of section. The cytoplasm of these giant cells often contained phagocytized material which most often appeared to be degenerated stromal cells. Examination of the contents of the submandibular triangle revealed metastatic tumor in one of three lymph nodes. The metastatic tumor showed the same relationship of malignant stromal cells and benign-appearing giant cells as seen in the

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Fig. 6. Photomicrograph demonstrating high rate of mitotic activity of stromal cells. One of the giant cells shows prominent phagocytic activity. (Hematoxylin and eosin stain. Original magnification, X250.)

Fig. 7. Interlacing bundles of spindle cells typical of fibrosarcoma. magnification, X 250.) primary lesion. The mandibular lesion was diagnosed as malignant giant cell tumor of bone with the surgical margins apparently free of tumor. Subsequent

cllnical course

One month following the initial resection, the patient developed drainage from the surgical incision and antibiotic

(Hematoxylin

and eosin stain. Original

therapy was initiated. Left facial swelling developed 2 months following the initial resection and the rib graft was removed. During the surgical procedure tumor was curetted from the graft bed and submitted for microscopic examination. The sections revealed a proliferation of stromal cells and benign-appearing multinucleated giant cells having the same

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Fig. 8. Photomicrograph Original magnification,

Oral Sure. February, 198u1

demonstrating X400.)

large number of mitoses in recurrent tumor (Hematoxylin

Fig. 9. Postmortem sample of tumor demonstrating eosin stain. Original magnification, X250.)

marked pleomorphism

over-all configuration as the initial resection specimen. However, the stromal cells in the recurrent lesion appeared increased in size, with more prominent variation in nuclear size and shape (Fig. 8). The number of mitoses was dramatically increased (usually more than ten and sometimes as many as twenty per high-power field). The patient received 5,000 rads of cobalt-60 radiation, but the lesion continued to enlarge dramatically, producing severe left facial deformity with extensive ulceration of the

and eosin stain.

of stromal cells. (Hematoxylin

and

overlying skin. Radiographic examination revealed multiple pulmonary metastases, and the patient died 6 months following his initial presentation. The exact cause of death could not be ascertained, as the family refused permission for an autopsy. The family would allow postmortem samples to be taken from the recurrent mandibular neoplasm, however, and microscopic examination revealed extensive tumor necrosis. The viable tumor showed an admixture of markedly pleomorphic, hyperchro-

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matic stromal cells and benign-appearingmultinucleated giant cells(Fig. 9). No osteoidor bonewasidentified. DISCUSSION

Investigators in the nineteenth and early twentieth centuries debatedthe benign versusmalignant nature of giant cell tumors. (See reviews by Coley” and by Stewart and co-authors.g) Much of their confusion can be attributed to the worrisome behavior of “benign” giant cell tumors which may be locally aggressive, recur in 30 percentI to 62 percent’ of the cases,invade soft tissues,‘I and rarely metastasizeto the lungs while maintaining a benign histologic appearance.l2 In 1940 Jaffe and associatesi were able to place the subject in perspective by clearly defining giant cell tumor of bone as a distinct clinicopathologic entity and documenting a spectrum of biologic behavior for giant cell tumor of bone ranging from benign to malignant. These authors proposeda system of grading giant cell tumors in which Grade I tumors were thosewhich contained uniformly benign-appearing stromal cells and behaved in a benign fashion. Grade III giant cell tumors contained frankly malignant stromalcells and pursueda malignant course. Grade II giant cell tumors were intermediate between Grades I and III in histopathology and prognosis. Although someauthors27ii have found grading to be of no value, others”, I4 still defend its value in determining prognosis. While the malignant transformation of giant cell tumors has been reported by a number of authors, the nature of this transformation is lessclear. Those cases which undergo transformation following surgical treatment alone are rare but clearly indicate that radiation is not a prerequisite for the transformation. The sarcomawhich develops following radiation treatment of a benign giant cell tumor may represent malignant transformation of the original giant cell tumor or an entirely independent radiation-induced sarcoma. The distinction between thesetwo possibilities may, in any one case, be extremely difficult to establish.*j The case reported by Sabanas and associatesl’j provides an example of the difficulty involved in making this distinction. Those authors reported the caseof a boy who developed an osteosarcomaof the maxilla 7 years following radiation treatment of a central giant cell granuloma which occurred when he was 9 years of age. The osteosarcomawhich developed most likely represents an independent radiation-induced sarcomarather than malignant transformation of the pre-existing giant cell granulomaand should not be labeled a malignant giant cell “tumor. ” The literature concerning primary malignant giant cell tumors of bone is difficult to interpret. As indicated in the introduction, some authors have misused the

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diagnosisfor osteosarcomascontaining a large number of benign-appearingmultinucleated giant cells. Other authorsI’ consider casesof malignant giant cell tumor of bone to representosteosarcomaswhich are so undifferentiated that they are unable to produce osteoid or bone, The criteria for the diagnosisof malignant giant cell tumor of bone specified by Dahlin and associates* (see introduction) have helped to eliminate the haphazard application of the diagnosis. Unfortunately, there is still disagreementamong authors concerning the inclusion of sometypes of sarcomain the category of primary malignant giant cell tumor of bone. While Dahlin and associate? are willing to accept osteosarcomas containing areas of typical benign giant cell tumor as primary malignant giant cell tumors, others’” prefer to classify these tumors as osteosarcomas. In 1979 Nascimento and colleagues’j reported eight casesof primary malignant giant cell tumor of bone which satisfied the diagnostic criteria of Dahlin and his co-workers.2 These authors excluded from their study any sarcomashowing production of bone by malignant stromal cells. Six of their casesinvolved the epiphyseal end of a long bone, one caseinvolved the scapula, and one the fourth metacarpalbone. The age range of these patients was quite large (17 to 76 years), with an average age over 30 years. The prognosisfor these patients appeared more favorable than for patients with secondary malignant giant cell tumors of bone. A discussionof malignant giant cell tumors of the jawbones is complicated by the controversy surrounding the relationship of giant cell tumors to central giant cell granulomas. While some authors’“, ig have considered giant cell tumors and giant cell granulomas of the jawbones to representseparateentities, other investigators” have presented rather convincing evidence that theseare identical lesions. For the purposesof our discussion,we accept the argument that theserepresent essentially the same lesion and consider malignant giant cell tumors involving the jawbones to be analagous to those involving other bonesof the skeleton. Although malignant giant cell tumors of bone represent 8.7 percent’ to 30 percent’ of giant cell tumors outside the jawbones, they appear to be extremely rare in the mandible and maxilla. Waldron*O reviewed the literature prior to 1953 and was unable to find a single reported case of malignant giant cell tumor in the jawbones. Since that review there have been four articles21-24which have presentedfour casesof malignant giant cell tumors in the mandible and one in the maxilla. Cones*l reported a case of a 65year-old man with Paget’s diseaseof bone who developed a giant cell tumor of the mandible with features suggestive of malignancy. The patient died 6 months following his

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initial presentation after unsuccessfultreatment involving surgery and radiation. Autopsy revealed the recurrence at the primary site and a metastaticlung nodule to be composedentirely of chondrosarcomawith no evidence of giant cell tumor. This caseappearsto qualify as a converted or (secondary) malignant giant cell tumor of bone, since the lesion presentedinitially as a giant cell tumor and subsequentlyunderwent malignant transformation. The malignant transformation of giant cell tumor to pure chondrosarcomahas, to our knowledge, not been recorded by another investigator. This fact, combined with the very short time for the transformation to take place, must raise the question of whether the lesion at the time of initial presentation may have been a chondrosarcomacontaining benignappearing multinucleated giant cells. The casereported by Hayward** began with a giant cell lesion of the mandible in a 14-year-old boy. The lesion recurred as an osteoblastomaproducing cartilage, osteoid, and bone. The patient eventually developed radiographic evidence of lung metastasesand died 7 months after his initial presentation. The total absenceof photomicrographsmakesthis report extremely difficult, if not impossible, to interpret. Waldron and Shafer” had the opportunity to review material from this caseand consideredthe most appropriate diagnosis to be osteosarcoma,not malignant giant cell tumor. The two casesreported by Hamlin and Lund23also lack documentation by photomicrographs. The authors suggestedthat one case (No. 14) would be best diagnosed as a neurogenic sarcoma with a few reactive giant cells. Their other case(No. 13) would appear to representmalignant transformation of a giant cell tumor following radiation treatment but, asthe authors stated, this must remain a matter of speculation since the pathology material showing the giant cell tumor was not available for study. Welsh and Meyer24 reported the ultrastructure of a malignant giant cell tumor of the maxilla. The neoplasmpresentedinitially as a benign giant cell tumor in a 70-year-old black man. The lesion recurred 7 months later as a questionably malignant giant cell tumor and recurred a second time, 18 months following initial presentation, as a malignant giant cell tumor. The patient died postoperatively without evidence of metastases. Unfortunately, light photomicrographs detailing the malignant transformation were not provided. The present case involves the first documented primary malignant giant cell tumor to be reported in the jawbones. This mandibular neoplasm contained areas typical of giant cell tumor (Fig. 5) admixed with both giant cell tumor containing malignant stromal cells (Fig. 6) and fibrosarcoma (Fig. 7). Therefore, it satisfiesthe criteria of Dahlin and associates.*

Oral Surg. February, 1981

The differential diagnosisin a casesuch as this must include two sarcomasof bonewhich may contain numerous benign-appearing multinucleated giant cells-osteosarcoma’ and malignant fibrous histiocytoma of bone.25Osteosarcoma as a diagnosis seemsinappropriate, since the malignant stromal cells showed no evidence of producing osteoid or bone. Malignant fibrous histiocytoma of bone must be given more serious consideration as a diagnostic possibility. Nascimento and associates’jidentified areasin some of their cases of primary malignant giant cell tumor of bone where the malignant stromal cells adopted a storiform pattern typical of malignant fibrous histiocytoma. In the present case under study focal areas (Fig. 4) show a storiform pattern, but we, like Nascimento and colleagues,‘” regard the areastypical of giant cell tumor in a sarcoma to be diagnostic of malignant giant cell tumor of bone, not malignant fibrous histiocytoma. The presentcaseunder study also lacked the pleomorphic giant cells so commonly seenin malignant fibrous histiocytoma. REFERENCES 1. Hutter, R. V. P., Worcester, J. N., Jr., Francis, K. C., Foote, F. W., Jr., and Stewart, F. W.: Benign and Malignant Giant Cell Tumors of Bone, Cancer 15: 653-690, 1962. 2. Dahlin, D. C., Cupps, R. E., and Johnson, E. W., Jr.: Giant Cell Tumor: A Study of 195 Cases, Cancer 25: 1061-1070, 1970. 3. Goldenberg, R. R., Cambell, C. J., and Bonfiglio, M.: Giant Cell Tumor of Bone, J. Bone Joint Surg. 52A: 619-663, 1970. 4. Windeyer, B. W., and Woodyatt, P. B.: Osteoclastoma, J. Bone Joint Surg. 31B: 252-267, 1949. 5. Murphy, W. R., and Ackerman, L. V.: Benign and Malignant Giant Cell Tumors of Bone, Cancer 9: 317-339, 1956. 6. Mnaymneh, W. A., and Ghandur-Mnaymneh, L.: Giant Cell Tumor of Bone, Prog. Clin. Cancer 3: 245-280, 1967. I. Troup, J. B., Dahlin, D. C., and Coventry, M. B.: The Significance of Giant Cells in Osteogenic Sarcoma: Do They Indicate a Relationship Between Osteogenic Sarcoma and Giant Cell Tumor of Bone? Proc. Staff Meet. Mayo Clin. 35: 179-186, 1960. 8. Coley, W. B.: Malignant Changes in the So-Called Benign Giant Cell Tumor, Am. J. Surg. 28: 768-820, 1935. 9 Stewart, F. W., Coley, B. L., and Farrow, J. H.: Malignant Giant Cell Tumor of Bone, Am. J. Pathol. 14: 515-535, 1938. 10 Huvos, A. G.: Bone Tumors: Diagnosis, Treatment and Prognosis, Philadelphia, 1979, W. B. Saunders Company, pp. 265291. 11. Larsson. S. E., Lorentzon, R., and Boquist, L.: Giant Cell Tumor of Bone, J. Bone Joint Surg. 57A: 167-173, 1975. 12. Gresen, A. A., Dahlin, D. C., Peterson, L. F. A., and Payne, W. S.: “Benign” Giant Cell Tumor of Bone Metastasizing to Lung, Ann. Thorac. Surg. 16: 531-535, 1973. 13. Jaffe, H. L., Lichtenstein, L., and Portis, R. B.: Giant Cell Tumor of Bone, Arch. Pathol. 30: 993-1031, 1940. 14. Lichtenstein. L.: Bone Tumors, ed. 5, St. Louis, 1977, The C. V. Mosby Company, pp. 127-159. 15. Nascimento, A. G., Huvos, A. G., and Marcove, R. C.: Primary Malignant Giant Cell Tumor of Bone, Cancer 44: 13931402, 1979. 16. Sabanas, A. O., Dahlin, D. C., Childs, D. S., Jr., and Ivins, J. C.: Postradiation Sarcoma of Bone, Cancer 9: 528-542, 1956. 17. Waldron, C. A., and Shafer, W. G.: The Central Giant Cell

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Reparative Granuloma of the Jaws, Am. J. Clin Pathol. 45: 437-447, 1966. Shklar, C., and Meyer, 1.: Giant-Cell Tumors of the Mandible and Maxdla, ORAL SURG. 14: 809-827, 1961. Austin, L. T., Jr., Dahlin, D. C., and Royer, R. Q.: Giant Cell Reparative Granuloma and Related Conditions Affecting the Jawbones, ORAL SURG. 12: 12851295, 1959. Waldron, C. A.: Giant Cell Tumors of the Jawbones, ORAL SURG. 6: 1055-1064, 1953. Cones. D. M. T.: An Unusual Bone Tumour Complicating Paget‘s Disease, J. Bone Joint Surg. 35B: 101-105. 1953. Hayward, J. R.: Malignant Giant Cell Tumor of the Mandible: Report of a Case. J. Oral Surg. 17: 75-80, 1959. Hamlin, W. B., and Lund, P. K.: “Giant CeH Tumors” of the Mandible and Facial Bones, Arch. Otolaryngol. 86: 658-665, 1967.

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24. Welsh, R. A., and Meyer, A. T.: Nuclear Fragmentations and Associated Fibrils in Giant Cell Tumor of Bone, Lab. Invest. 22: 63-72, 1910. 25. McCarthy, E. F., Matsuno, T., and Dorfman, H. D.: Malignant Fibrous Histiocytoma of Bone: A Study of 35 Cases, Hum. Pathol. 10: 57-70, 1979. Reprint reqursts to: Dr. Albert M. Abrams Section of Pathology University of Southern California 925 West 34th St. Los Angeles, Calif. 90007

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