Multicentric Giant Cell Tumor of Bone: Clinicopathologic Analysis of Thirty Cases

Hoch, Benjamin MD; Inwards, Carrie MD; Sundaram, Murali MD; Rosenberg, Andrew E. MD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.E.01111
Scientific Articles
Abstract

Background: Giant cell tumor of bone accounts for 4% to 5% of primary bone tumors. Approximately 1% of cases present as multiple synchronous or metachronous lesions. In this study, we describe the clinicopathologic features of thirty cases of multicentric giant cell tumor.

Methods: Thirty patients who had two or more separate lesions that had been pathologically confirmed to be giant cell tumors were identified. Radiographs were reviewed to evaluate the characteristics and locations of the tumors. Histologic reexamination was performed to document morphologic features. Clinical information and follow-up data were obtained from the medical records.

Results: The male:female ratio was 1:2, with an average age at presentation of twenty-one years. Fifty-nine percent of the patients were younger than twenty years of age. There were ninety-four tumors in the series, with an average of three (range, two to nine) per patient. Most tumors had arisen in the long bones. Six patients had synchronous ipsilateral involvement of the distal part of the femur and the proximal part of the tibia. Radiographically, the tumors in long bones manifested as expansive lytic lesions involving the metaphysis and extending into the epiphysis. A minority of the tumors were confined to the metaphysis, had features of a fibro-osseous or bone-forming lesion, or arose in skeletally immature patients. Secondary histopathologic changes including fibrohistiocytic regions, reactive bone formation, or aneurysmal bone cyst-like changes were not uncommon. Most tumors were treated with curettage (64%) or resection (22%). The recurrence rate was similar to that of solitary giant cell tumors. Metastatic disease developed in three patients, and two patients had malignant transformation.

Conclusions: Multicentric giant cell tumors occur more often in younger patients than do solitary giant cell tumors, and they frequently present as synchronous lesions around the knee. Some tumors appear as bone-forming or fibroosseous tumors on imaging studies as a result of fibrohistiocytic regions and reactive bone formation. The risk of recurrence depends on the type of surgery that is performed.

Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Author Information

1 Department of Pathology, Mount Sinai Medical Center, Box 1194, One Gustave L. Levy Place, New York, NY 10029. E-mail address: benjamin.hoch@mountsinai.org

2 Mayo Clinic, 200 First Street S.W., Rochester, MN 55905

3 The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195

4 Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114

Article Outline

Giant cell tumor of bone is a well-recognized clinicopathologic entity and accounts for 4% to 5% of primary bone tumors in the United States1. It is considered a benign neoplasm that can recur locally following curettage, and it rarely metastasizes to the lungs. Giant cell tumor of bone was initially described by Jaffe et al. in 19402, and subsequent studies3-11 have expanded and confirmed the initial observations of those authors. Giant cell tumor of bone typically presents as a solitary lytic lesion that spans the metaphyseal-epiphyseal region of long bones of adults. In approximately 1% of cases, however, it manifests as multiple synchronous or metachronous lesions in single or multiple bones3-10,12-35. Those cases have been designated multicentric giant cell tumors, and their pathogenesis is unknown. Their clinical and radiographic differential diagnosis usually includes a variety of polyostotic skeletal lesions such as brown tumor, Paget disease, osteomyelitis, nonossifying fibroma, enchondromatosis, fibrous dysplasia, giant cell reparative granuloma, Langerhans cell histiocytosis, vascular tumor, osteosarcoma, hematopoietic malignant tumor, and metastasis. A diagnosis of pigmented villonodular synovitis eroding bone may be considered when the ends of the bones on both sides of a joint are involved. In most situations, a definitive diagnosis requires histopathologic confirmation. To our knowledge, forty-eight cases of multicentric giant cell tumor have been reported in the literature, and most reports have been either case studies or have involved small series12-31,36,37. In this investigation, we describe our experience with the clinicopathologic findings of thirty cases of multicentric giant cell tumor, the largest series to date to our knowledge, in order to expand the knowledge about this unusual tumor.

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Materials and Methods

The hospital and consultation files of the pathology departments at the Mayo Clinic (Rochester, Minnesota) and Massachusetts General Hospital (Boston, Massachusetts) were searched for patients who had been diagnosed with a giant cell tumor between 1950 and 2002. Patients who had two or more separate bone lesions that had been confirmed to be giant cell tumors on histologic examination on the basis of conventional histopathologic criteria2,38 were defined as having multicentric giant cell tumor. Tumors were classified as being synchronous when multiple tumors had been discovered at the initial presentation or when a second tumor had been diagnosed within six months after the first. If the second tumor developed more than six months after the first lesion, the lesions were considered to be metachronous. A cohort of thirty patients, which included nine who had been reported on previously25, was identified. All cases were initially diagnosed by an experienced bone pathologist. For this study, routine hematoxylin and eosin-stained slides were available for review for twenty-nine of the thirty patients. Histologic reexamination of those slides was performed to confirm the diagnosis and to identify any unusual morphologic features. Radiographs of tumors were available for twenty-four patients, and they were reviewed to determine the location and characteristics of the tumors. Clinical information and follow-up data were obtained from medical records, original pathology reports, and correspondence letters. Clinical information was available for twenty-nine of the thirty patients, and follow-up data were available for twenty-seven of the thirty patients. A diagnosis of hyperparathyroidism was excluded on the basis of laboratory data or radiographic findings in each case. Neither radiographic nor histologic grading of the tumors was performed.

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Results

Clinical Features (see Appendix)

The study included nineteen female patients (66%) and ten male patients (34%); the gender of one patient was unknown. The average patient age at the time of presentation of the first tumor was twenty-one years (range, eleven to sixty-two years). Seventeen (59%) of the patients were younger than twenty years of age; thirteen of the seventeen were less than sixteen years of age, and thirteen were female. Twenty-eight percent (eight) of the patients in the series were in the third decade of life, 10% were in the fourth decade, and only one patient was older than forty years of age at the time of the initial presentation. A total of ninety-four tumors were identified in the thirty patients, who had an average of three tumors (range, two to nine tumors) each. Thirteen patients (43%) had only two tumors. Eleven patients (37%) had synchronous tumors, and seven of them (23% of the series) had multiple tumors discovered at the initial presentation. The average time between the diagnosis of the first tumor and the discovery of the second in the nineteen patients with metachronous tumors was 5.3 years (range, one to sixteen years). In six patients, a metachronous lesion developed within two years after the first tumor. The maximum time span over which any one patient had the development of two or more tumors was twenty-three years.

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Location

Most tumors arose in long bones; 31% of the tumors developed around the knee, with almost equal involvement of the distal part of the femur and the proximal part of the tibia (Fig. 1). Eight patients (27%) had ipsilateral involvement of the distal part of the femur and the proximal part of the tibia, and in six of them these were synchronous tumors. None of these tumors extended across the knee joint. The next most frequent locations were the distal part of the radius (10%), proximal part of the humerus (8%), distal part of the tibia (8%), distal part of the ulna (7%), proximal part of the femur (5%), and proximal part of the fibula (4%). Six tumors involved vertebral bodies, and five of them were localized to the cervical spine. Eight tumors in seven patients occurred in the bones of the hands and feet. One of these patients had involvement of two bones of the same hand over a nine-year period. Few tumors arose in the pelvic bones, and the ribs and skull bones were rarely involved. Rarely, more than one tumor was discovered in a single bone; one patient had three separate lesions involving the left ulna over a twelve-year period.

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Radiographic Findings

Tumors in the long bones usually manifested as an expansile lytic mass extending from the metaphysis through the closed growth plate and into the subchondral region of the epiphysis (Figs. 2 and 3). The lesion margins were generally well-defined (a narrow zone of transition) and lacked sclerosis. The cortices were either expanded or destroyed by tumor, which frequently extended into the adjacent soft tissues. Twelve tumors were either diaphyseal-metaphyseal or metaphyseal in location. Eight of these were in skeletally immature patients with open growth plates, and seven exhibited prominent sclerosis and mineralization, which caused them to mimic a fibro-osseous lesion such as fibrous dysplasia. The distal part of the femur was the most common location for such unusual lesions (Figs. 4 and 5).

Tumors of the metacarpals, metatarsals, and phalanges usually were purely lytic and extended to the end of the bone. Tumors arising in other small bones of the hands and feet and those in the pelvis, skull, and vertebrae presented as nonspecific lytic lesions.

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Histologic Findings

All of the multicentric giant cell tumors contained foci that exhibited the morphologic features diagnostic of giant cell tumor. These areas consisted of sheets of uniform oval to polygonal mononuclear cells admixed with numerous large osteoclast-like giant cells. The nuclei of the mononuclear and giant cells were morphologically similar to one another and were round to oval with fine to slightly vesicular chromatin and with distinct nucleoli. The giant cells frequently contained more than twenty nuclei. The cytoplasm of the mononuclear cells was eosinophilic and the cell membranes were not well-defined, creating a syncytial appearance (Fig. 6). In some areas, the mononuclear cells were spindle-shaped, resembling fibroblasts, and were enmeshed in a collagenous stroma that also contained scattered aggregates of foamy histiocytes. The spindle cells were frequently arranged in a storiform pattern and were most prominent in the periphery of the tumors. Nine patients had tumors with extensive fibroblastic and fibrohistiocytic regions, and one of those patients had tumors involving the distal part of the femur and the patella that were composed entirely of the fibrohistiocytic component (Fig. 7). One tumor exhibited limited cytologic atypia in which the round and oval mononuclear cells had enlarged hyperchromatic nuclei with irregular nuclear borders. These atypical cells were only focally present within the tumor, were not mitotically active, and often were associated with areas of hemorrhage. Because of these features, such changes were considered to be degenerative in nature. This tumor did not recur or metastasize following curettage.

In general, the mononuclear cells, regardless of their morphology, exhibited occasional mitoses; mitotic figures were numerous in only a minority of the tumors. Other secondary findings in the tumors included aneurysmal bone cyst-like changes, which were present in nine tumors from six patients, and reactive bone formation, which was present in most tumors but was especially prominent in areas associated with fibrohistiocytic or aneurysmal bone cyst-like changes. Tumors that resembled a fibro-osseous lesion radiographically were among the tumors with prominent fibrohistiocytic components and abundant reactive bone with or without aneurysmal bone cyst-like changes (Figs. 8-A and 8-B).

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Treatment and Recurrence

The majority of tumors (62%), particularly those involving long bones or bones of the hands and feet, were initially treated with curettage and bone-grafting. A tumor in the proximal part of the tibia was treated with radiation therapy and curettage, and a tumor in the acetabulum was treated with cryotherapy and curettage. Methylmethacrylate was used following curettage of one tumor of the proximal part of the tibia. Use of adjuvant therapies was not documented for any of the remaining tumors treated with curettage. Twenty-one tumors (22%) were initially treated with wide excision. These lesions generally involved bones that could be sacrificed without a substantial loss of function, such as the distal part of the radius or the proximal part of the fibula. Two tumors in the cervical spine were treated with radiation therapy alone. Two sphenoid tumors were treated with partial excision followed by adjuvant radiation therapy, and one skull tumor was treated with partial excision, adjuvant radiation therapy, and chemotherapy. One tumor in the left lateral cuneiform bone was initially treated with below-the-knee amputation, possibly because it was thought to be a more aggressive tumor on the basis of clinical findings.

Patients were generally followed with routine periodic plain radiography of the affected bone to look for tumor recurrence. Twenty-four (26%) of the ninety-four tumors recurred, and twenty of the thirty patients had recurrence of at least one tumor. The average time to recurrence was 2.5 years (range, two months to nine years), and twelve patients had a recurrence in less than two years. Fourteen patients had only one recurrence of a single tumor. One of these tumors was a C2 vertebral lesion that had been treated initially with radiation therapy alone. Another was a distal ulnar tumor that had been treated initially with excision; it recurred in the soft tissues. The remaining twelve tumors were initially treated with curettage, and all but one involved a long bone. In three other patients, one tumor recurred multiple times following the initial curettage. These cases included five recurrences of a C2 vertebral tumor (Case 10; see Appendix), each treated with curettage over a thirteen-year period; two recurrences of a distal radial tumor (Case 11), one treated with curettage with wrist fusion and the subsequent recurrence treated with excision over a seven-year period; and two recurrences of a metatarsal tumor (Case 26), one treated with curettage and the subsequent recurrence treated with amputation over a five-month period. Multiple tumors of long bones recurred in three patients (Cases 2, 6, and 23). All but one of these recurrences were treated with either excision or amputation. One of these patients (Case 23) had a soft-tissue recurrence of a distal femoral lesion following an initial curettage and had multiple recurrences of an ipsilateral proximal femoral tumor following several curettage procedures. None of the three tumors treated with adjuvant cryotherapy or methylmethacrylate packing recurred.

Seven patients with a total of eighteen tumors for which there were follow-up data had no recurrences. The follow-up period for these patients, beginning from the discovery of the initial tumor, ranged from one year and two months to sixteen years (average, 7.7 years). These tumors involved a variety of bones, including long bones, bones of the hands and feet, pelvic bones, and vertebrae. All of these tumors were initially treated with curettage or excision, except for one tumor of the left lateral cuneiform, which was treated with amputation.

No follow-up data were available for three patients who presented with synchronous tumors (Cases 18, 20, and 27; see Appendix).

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Outcome

Follow-up data beginning from the discovery of the most recent tumor or recurrence were available for twenty of the thirty patients. The follow-up period ranged from two months to thirty-five years (average, six years). Other than a patient who died of osteosarcoma (as described below) and a patient with pulmonary metastasis who died of influenza, these patients had no additional recurrences or new tumors.

Metastatic disease to the lungs developed in three patients (Cases 11, 13, and 16; see Appendix). The time from discovery of the initial giant cell tumor to the detection of the pulmonary metastases ranged from five to eight years (average, 6.3 years). These patients had a total of eight tumors, in the long bones, pelvic bones, and ribs; five tumors were treated with curettage, and three were excised. All three patients had had a local recurrence of one of the tumors; one of those recurrences was in the soft tissues and followed excision of a distal ulnar tumor. In all three patients, the initial pulmonary metastatic tumor was excised and histologically confirmed to be giant cell tumor. One patient had new pulmonary metastases two years after excision of the original tumor. These lesions remained stable until the patient died of influenza six years later. Another patient was disease-free at the time of follow-up, 1.5 years after the excision of the lung metastasis. The third patient was lost to follow-up. None of the patients had metastatic disease beyond the confines of the lungs.

Osteosarcoma developed in one patient thirteen years after the diagnosis of multicentric giant cell tumor. This patient had presented, at the age of thirty-five years, with synchronous tumors involving the distal part of the femur and the proximal part of the tibia, which were treated with excision of the femoral tumor and curettage of the tibial lesion. No other tumors or evidence of metastatic disease were documented at the time of the initial presentation. The patient was clinically stable until thirteen years later, when he presented with additional synchronous tumors involving the distal part of the ulna, the second phalanx, and the proximal part of the fibula. The fibular lesion showed areas of giant cell tumor and high-grade osteosarcoma. The patient died one year later of metastatic osteosarcoma to the lungs. In another patient, an intermediate-grade fibrosarcoma developed in a recurrent tibial tumor.

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Discussion

Multicentric giant cell tumor is rare and accounts for <1% of all cases of giant cell tumor of bone3-10,12-35. We believe that we have reported on the largest series of multicentric giant cell tumors to date, as most published reports on this condition have been single case descriptions17,19,27,28,31,33,34 or studies of small series22,25,32.

In our cohort, female patients outnumbered male patients by a ratio of almost two to one. This gender distribution is similar to that previously reported in the literature for both multicentric22,25,32,33 and solitary giant cell tumor4,9,13,35,38,39. The peak incidence of solitary giant cell tumor is in the third to fifth decades of life, with approximately 80% of patients being older than twenty years of age at the time of diagnosis4,13,35,39. In our series, the average age at presentation was twenty-one years, and 59% were younger than twenty years of age. Other investigators have also noted that patients with multicentric giant cell tumor are considerably younger than those with a solitary giant cell tumor22,25,32; however, this has not been a consistent finding33. One of our patients was a girl who presented with tumors at the ages of eleven and twelve years; to our knowledge, she was the youngest patient with multicentric giant cell tumor reported to date.

Eleven (37%) of our patients presented with synchronous tumors. Six of these cases involved the knee (the distal part of the femur and proximal part of the tibia of the same limb). The prevalence of synchronous tumors and their predilection for the knee region have not been previously recognized, to our knowledge. Interestingly, we found that patients who had multicentric giant cell tumor generally had it relatively early in the course of the disease, as 56% of our patients had more than one tumor at the initial presentation or had the development of additional tumors within two years after the discovery of the first giant cell tumor. However, there may be a lag time of as long as sixteen years between the first and second tumor, and additional lesions can develop for as long as twenty-three years. Overall, patients with multicentric giant cell tumor generally have two or three lesions, but in our experience patients have had as many as nine. At least one patient with ten tumors has been described in the literature40.

The anatomic distribution of multicentric giant cell tumors in this series (Fig. 1) is similar to that of solitary giant cell tumors, with a few exceptions4,8,13,35,38,39. Most of the tumors in our patients arose in the long bones of the lower extremity, predominantly around the knee, followed by the proximal part of the humerus and the distal part of the radius. Previous reports have emphasized the high frequency at which multicentric giant cell tumor affects the hands12,22,33. In fact, in some series, as many as 20% to 39% of cases of multicentric giant cell tumor have had at least one focus in the hand and 18% of patients with giant cell tumor affecting the hand have had polyostotic lesions12,32,33. However, a compilation of some investigators' work has shown that only 0.4% to 3.9% of multicentric giant cell tumor lesions affected the hands4,12,22,25,27. In our series, four tumors of the hand (4%) and four tumors of the foot (4%) occurred in three patients (10%) and four patients (13%), respectively. This frequency of hand and foot involvement is similar to that reported by the aforementioned investigators and is greater than the 2% frequency associated with solitary tumors4,8,12,13,35,38,39. None of the tumors in our series arose in the sacrum, a site where 9% of solitary tumors originate38.

In most cases, individual lesions of multicentric giant cell tumor have radiographic features that are essentially indistinguishable from those of a solitary giant cell tumor. In long bones, multicentric giant cell tumors generally present as eccentric lesions predominantly involving the metaphysis and epiphysis with extension into the subchondral region of the bone (Figs. 2 and 3). Interestingly, our group included eight patients with a total of twelve tumors (13% of all tumors) that were restricted to the metaphyseal or diaphyseal-metaphyseal regions of long bones (Fig. 4). The distal part of the femur was the most common location for these unusual lesions. This is the same anatomic site as that of solitary lesions that are confined to the metaphysis13. Tumors limited to the metaphysis account for 1% to 9% of all solitary giant cell tumors13,35. In a previous report, metaphyseal lesions accounted for five (14%) of thirty-five cases of multicentric giant cell tumor25 (two of these patients, who had a total of three tumors, were included in the present series). The age range for our patients with metaphyseal lesions was twelve to fifteen years, and all but one patient was female. In our series, four of six patients with radiographically confirmed open growth plates had metaphyseal lesions—that is, half of the patients with metaphyseal lesions were skeletally immature as shown by imaging studies. Although the actual number may be smaller, 5.7% of solitary giant cell tumors occur in skeletally immature patients41. In the series reported by Kransdorf et al.41, 96% of solitary giant cell tumors in skeletally immature patients were predominantly confined to the metaphysis, and others have demonstrated that metaphyseal giant cell tumor can cross at least a partially open physis42. As our series demonstrates, lesions of multicentric giant cell tumor can be confined to the metaphysis in either skeletally mature or immature patients and metaphyseal lesions occur more frequently in patients with multicentric giant cell tumor than in those with solitary giant cell tumor.

A small minority of tumors exhibited sclerosis and evidence of mineralization, unusual radiographic features for a conventional giant cell tumor, suggesting a fibro-osseous or bone-forming tumor (Figs. 3 and 4). The histologic correlate to the sclerosis was abundant reactive bone that was prominent in fibrohistiocytic and aneurysmal bone cyst-like areas (Figs. 7 and 8-A, 8-B). Such lesions in a patient with polyostotic disease can result in diagnostic confusion, particularly with entities such as fibrous dysplasia. This finding emphasizes the need for histologic examination to establish the diagnosis of multicentric giant cell tumor.

In general, multicentric giant cell tumor is histologically indistinguishable from solitary giant cell tumor (Fig. 6). All of our cases had areas diagnostic of giant cell tumor2,38; however, some also contained fibroblastic and fibrohistiocytic areas, which were usually only a minor component of the tumor and tended to surround regions of classic giant cell tumor (Fig. 7). This same fibrohistiocytic proliferation is an accepted component of solitary giant cell tumor, in which it is seen in varying amounts. In one of our patients with multicentric giant cell tumor, however, the fibrohistiocytic proliferation dominated the histologic picture of tumors in the proximal part of the femur and the proximal and distal parts of the tibia. This patient also had lytic lesions in the distal part of the femur and in the patella that were composed solely of the benign fibroblastic and fibrohistiocytic components. Such lesions have been reported in other patients with multicentric giant cell tumor22 and may represent giant cell tumor in a stage of degeneration or involution in which the diagnostic areas are obscured by the fibrohistiocytic tissue. One case exhibited focal cytologic atypia with a benign clinical course. This type of atypia is probably of a degenerative or “pseudoanaplastic” nature and has been described in other benign bone tumors43.

The overall tumor recurrence rate of 26% in our series was similar to that reported in the literature for solitary giant cell tumors13,39. Of the patients for whom follow-up information was available, 74% had recurrence of at least one tumor. It appears that the single most important factor related to the risk of recurrence in our patients was the incompleteness of surgical removal, as the recurrence rate was highest (37%) for lesions that had been initially treated with curettage. In comparison, wide excision was associated with a recurrence rate of 5%. It is important to note that adjuvant thermal or chemical therapies were not used for the vast majority of patients in whom the multicentric giant cell tumor was treated with curettage; this accounts for the slightly higher recurrence rate seen with these tumors as compared with the recurrence rates of 8% to 34% seen with solitary giant cell tumor for which adjuvant therapies were utilized44. Soft-tissue recurrence, which can occur many years after initial excision of a solitary giant cell tumor45, developed in two of our patients. In general, in our series, recurrences were treated with more aggressive surgical removal, including amputation; however, repeat curettage was effective in controlling some tumors. Three patients had tumors that were followed clinically without surgical intervention, and all of those tumors remained stable. Radiation therapy, although reserved for lesions that were not amenable to surgical removal, was generally ineffective in controlling the tumors.

Pulmonary metastasis of benign giant cell tumor is a well-documented and recognized phenomenon that occurs in <2% of patients with a solitary giant cell tumor35,46-49. To our knowledge, pulmonary metastases have not been previously reported in patients with multicentric giant cell tumor. Pulmonary metastases developed in three (10%) of our patients, at an average of 6.3 years after the discovery of the initial giant cell tumor. Combining our series of patients with those previously reported2-5,7-9,17,19,22,25,27,28,31-34,36, we determined that metastatic disease has developed in approximately 4% of patients with multicentric giant cell tumor. In our patients, the excised metastatic tumors had histologic features of conventional giant cell tumor and the patients had an indolent course similar to that of patients in whom a solitary giant cell tumor metastasizes.

Malignant transformation of giant cell tumor can be defined as a sarcoma, usually a fibrosarcoma or osteosarcoma, juxtaposed to areas of typical giant cell tumor or arising at the site of a previously treated benign giant cell tumor4,6,50,51. Up to 5% of solitary giant cell tumors undergo such malignant change, which may occur as many as twenty-five years after the primary treatment50,51. The overwhelming majority of these malignant transformations are associated with previous radiation therapy. Two of our thirty patients had malignant transformation with no previous radiation.

The clinical and radiographic similarities between solitary giant cell tumor and multicentric giant cell tumor suggest that the lesions of multicentric giant cell tumor arise independently, rather than being multiple sites of metastatic disease that develop from a single tumor. Specifically, individual lesions of multicentric giant cell tumor demonstrated characteristic radiographic features of giant cell tumor (e.g., a circumscribed lytic epiphyseal-metaphyseal lesion of a long bone), rather than a destructive pattern of a metastasis. This characteristic is similar to that of other polyostotic bone diseases in which separate lesions exhibit the radiographic features of the solitary form. Furthermore, the biological behavior of any given lesion in a patient was independent of the behavior of the other lesions, with the outcome being determined by how each tumor was treated. Disseminated metastatic disease did not develop even in patients with numerous skeletal tumors. The tendency of multicentric giant cell tumor to affect younger patients suggests that there may be a germ-line genetic abnormality that predisposes them to the development of multiple tumors. However, to our knowledge, familial forms of multicentric giant cell tumor have not been reported.

In summary, multicentric giant cell tumor is rare and most commonly affects long bones, particularly those around the knee. It tends to occur in younger patients and frequently manifests as synchronous lesions. In addition, lesions of multicentric giant cell tumor may have an unusual metaphyseal location and have characteristics of a fibroosseous lesion on imaging studies. Histologically, such tumors have abundant fibrohistiocytic and fibroblastic areas as well as reactive woven bone formation. Virtually all tumors have areas with typical histopathologic features of giant cell tumor. As is the case with a solitary giant cell tumor, the most aggressive behavior of the vast majority of multicentric giant cell tumors is local recurrence, although there have been rare cases of metastasis to the lungs as well as of malignant transformation. Because a variety of other primary bone lesions may also have a polyostotic presentation, the correct diagnosis relies on correlation of clinical and radiographic findings with confirmation of the diagnosis by histopathologic examination.

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Appendix

A table showing detailed information on all patients is available with the electronic versions of this article, on our web site at jbjs.org (go to the article citation and click on “Supplementary Material”) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM). ▪

The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Investigation performed at the Mayo Clinic, Rochester, Minnesota, and Massachusetts General Hospital, Boston, Massachusetts

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