Definition

Giant cell tumor of bone is a distinct, locally aggressive neoplasm composed of oval or plump, spindled mononuclear cells and uniformly distributed multinucleated giant cells. The tumor most frequently involves the ends of long bones in skeletally mature individuals. In other skeletal sites, it is almost invariably located in epiphyseal or epiphyseal-equivalent portions of bone.

Incidence and Localization

Giant cell tumor of bone accounts for approximately 4% of all primary bone tumors. Most patients are between ages 20 and 55 years, and the peak age incidence is in the third decade of life. Approximately 70% of cases are diagnosed in patients between ages 20 and 40 years, and it is very unusual for giant cell tumor to occur in patients younger than age 20 years or older than age 55 years. Although the diagnosis of giant cell tumor in these age groups should be treated with skepticism, the unusual occurrence of giant cell tumor in the first two decades of life, as well as its occasional presentation in patients older than age 55 years, has been reported.^{14,15,64–66,110} During the second decade of life, giant cell tumor usually occurs in female patients with fused growth plates.⁸⁰

Giant cell tumor is found most often in the epiphyseal ends of long tubular bones, with the distal end of the femur, proximal end of the tibia, and the distal end of the radius being the most frequent sites. It is uncommon in short tubular bones of the hands and feet. It is extremely rare in the vertebral bodies, but the sacrum is the most common site in the axial skeleton. Giant cell tumor is unusual in flat bones and ribs and very rarely affects craniofacial bones in the absence of Paget’s disease. The association of giant cell tumor with Goltz syndrome (focal dermal hypoplasia), a rare condition in which there are multiple congenital anomalies of skin, teeth, and bone, has been reported.¹⁰⁷ Its presence in two cases suggests that it may represent an integral element of the spectrum of anomalies observed in this very rare condition. Giant cell tumor may occur more frequently in Chinese people than in people who live in Western countries. The estimated rate in the Chinese population has been reported to account for about 20% of all primary tumors of bone.¹⁰⁶ The peak age incidence and the most common skeletal sites of involvement are shown in Figure 10-1.

The radiographic picture of a giant cell tumor is quite characteristic and diagnostic if present in the specific anatomic site of skeletally mature patients. Radiographs reveal a well-defined, eccentric, lytic subchondral lucency that involves the former epiphysis and metaphysis (Figs. 10-2 and 10-3). The cortex is frequently expanded and, at least focally, destroyed. In a small percentage of cases, there can be minimal periosteal reaction when the cortex is breached. The borders, although well defined, usually do not show marginal sclerosis, and trabeculation usually is not present. Occasionally, particularly in a weight-bearing bone, a giant cell tumor can show marked trabeculation and marginal sclerosis that produces the nontypical “soap bubble” appearance (Fig. 10-4). These changes can be correlated with the microscopic findings of extensive reactive fibrohistiocytic features (see later section). Pathologic fracture is found in 5% to 10% of giant cell tumors.³⁷ It may be the presenting clinical feature for patients with such tumors in weight-bearing bones (Figs. 10-5 and 10-6).

Some observers have proposed a radiologically based classification defining three main types of giant cell tumor: quiescent (type I), active (type II), and aggressive (type III).^14,15,29 These three varieties were referred to by Enneking²⁹ as surgical stages. The quiescent type is characterized by a lytic defect limited to the medullary cavity of the bone with minimal or no involvement of the cortical bone. Usually the defect is surrounded by a more or less clear rim of sclerosis, and fine trabeculation can be present. The active radiologic type is characterized by a thinned, expanded cortex and somewhat unclear margins. The aggressive radiologic type is characterized by a lytic defect with ill-defined margins, invasion of the cortex, and extension of the tumor into surrounding soft tissue. This radiologic classification of giant cell tumor has limited usefulness. So-called radiologic features of aggressiveness do not necessarily correlate with microscopic criteria of malignancy or the ultimate clinical behavior of the tumor. In the authors’ shared opinion, the terms quiescent, active, or aggressive should not be used even in the descriptive sense in reference to radiographic presentations of giant cell tumors. These are clinically irrelevant and misleading terms because they overlap with terms used to describe histologic features. Radiologic features of aggressiveness with huge destructive lesions, massive invasion into the cortex, and extension of the tumor into surrounding soft tissue are merely reflections of the stage of the disease. They do not necessarily correlate with aggressive histologic features in our experience.

Overlap in radiologic presentation with fibrosarcoma, malignant fibrous histiocytoma, multiple myeloma, and other destructive lesions can occur. Consequently, in many cases, the exact radiologic diagnosis of giant cell tumor cannot be made.

In very unusual instances, giant cell tumor may occur in the metaphyseal portion of bone without involving the epiphysis (Fig. 10-7). This may occur in young patients whose epiphyseal plates are still open. Nonepiphyseal localization of the lesion sometimes occurs in skeletally mature patients. So-called nonepiphyseal giant cell tumor represents a medical curiosity and is extremely rare.

Marked bone expansion and secondary aneurysmal bone cyst are frequent secondary changes seen in giant cell tumor that are best assessed by computed tomog­raphy and magnetic resonance imaging (Figs. 10-8 and 10-9).

Giant cell tumor of bone in its typical location and intact in its setting is soft, friable, fleshy, and red-brown with yellowish areas (Figs. 10-10 and 10-11). The tumor tissue is well demarcated and usually extends to the articular cartilage. The articular cartilage is unlikely to be invaded or perforated. The lesion usually occupies an eccentric position in the epiphyseal end of the bone. Its shaftward portion (i.e., advancing toward the medullary cavity) is usually more centrally located. It is delimited in its periphery by a thin layer of fibrous and reactive bone tissue. The cortical bone may not be involved, and the original contour of the bone may be preserved. However, more frequently, the original cortex has been destroyed, and the bone contour has been expanded. A thin shell of subperiosteal bone surrounding the periphery of the lesion is sometimes seen. Often there is gross evidence of hemorrhage, cyst formation, and necrosis. All these changes can be present in one tumor. There also may be evidence of pathologic fracture, most frequently involving the subchondral bony endplate. Hemorrhage and necrosis are particularly frequent and extensive in the weight-bearing bones (Fig. 10-10). They may be present with or without associated pathologic fracture.

Histologically, the basic pattern of giant cell tumor is that of a moderately vascularized stroma with oval or plump, spindle-shaped mononuclear cells uniformly interspersed with multinucleated giant cells (Figs. 10-12 to 10-14). The latter can have nuclei sometimes numbering 50 to 100 or even more, which are clustered in the middle of the cell (Figs. 10-14 and 10-15). The nuclei of stromal and giant cells are similar. They are round or oval with regular outlines, evenly distributed fine chromatin, and a prominent nucleolus. In addition to these two cell populations, occasional binucleated and trinucleated cells can be seen, suggesting a gradual transition of some mononuclear cells into multinucleated giant cells. This phenomenon can be seen particularly well in cytologic preparations in which whole intact cells are analyzed. Occasionally, stromal and giant cells may show pyknotic changes of the nuclei. Giant cells usually have dense eosinophilic cytoplasm with clear, sharp, oval borders. Occasionally, cells can be irregular in shape and vacuolated (Figs. 10-14 and 10-15).

Morphologically, several types of mononuclear stromal cell can be distinguished. The stroma can be composed of small or intermediate-sized oval cells. The spindle cells can be short and plump or elongated and fibroblast-like (Figs. 10-16 and 10-17). All these types of cells can be present in one tumor, sometimes accounting for a superficial impression of pleomorphism. True pleomorphism, not related to the presence of various types of stromal cells, should not be seen in a conventional giant cell tumor. The mitotic rate of mononuclear stromal cells can be quite high, but atypical mitoses are not present. There is no mitotic activity within multinucleated giant cells. No bone or cartilage matrix production by tumor cells is seen. The classic account of the histologic criteria for the diagnosis of giant cell tumors by Jaffe et al.⁴⁷ emphasized the relationship between clinical behavior and histologic evidence of spindle-cell predominance, focal attenuation of giant cells, and increased mitotic activity. This early histologic description included a numeric grading system (grades 1 through 3) that was designed to predict recurrent behavior and metastatic potential. Subsequent experience has shown that the use of numeric histologic grading lacks predictive value.

The classic microscopic pattern of giant cell tumor is frequently modified by a secondary reactive proliferation of fibrohistiocytic tissue, hemorrhage, necrosis, and aneurysmal bone cyst formation. Reactive fibrous tissue with a prominent storiform pattern and xanthogranulomatous reaction can be documented, at least focally, in nearly all appropriately sampled lesions. In some instances, reactive bone formation can be associated with these changes. Occasionally, fibrohistiocytic reaction massively replaces the underlying tumor so that it mimics lesions such as nonossifying fibroma or benign fibrous histiocytoma. In such instances, the analysis of radiographic data and additional sampling of the tumor are usually sufficient to document the existence of an underlying giant cell tumor. The presence of prominent, reactive fibroblastic tissue and xanthogranulomatous reaction correlates with radiographically prominent sclerotic margins and coarse trabeculations (Fig. 10-18).

Prominent focal reactive bone sometimes can be correlated with the presence of small cortical infractions. A shell of reactive bone usually is seen at the periphery of the lesion (Fig. 10-19). Although there is usually no periosteal reactive bone seen on radiographs, a thin rim of periosteal new bone formation is nearly always present microscopically. This peculiar capacity of giant cell tumor to induce reactive peripheral ossification is maintained in recurrences in soft tissues, in pulmonary implants, and even in the transplanted fragments of tumor tissue to athymic nude mice.⁶ In approximately 30% of resected giant cell tumors, intravascular invasion of tumor tissue can be observed in the adjacent soft tissue. This incidental finding does not appear to correlate with local aggressiveness or the development of pulmonary implants.

Hemorrhage, necrosis, or both usually result from fracture or mechanical compression. Old and fresh hemorrhage, as well as necrosis, can be present without any obvious cause and can be quite extensive. For unknown reasons, the mononuclear stromal cells usually develop the recognizable features of necrosis first. It is common to observe well-preserved giant cells in a completely necrotic stroma. Early necrotic changes associated with nuclear pyknosis and increased nuclear variability can mimic malignant change (Figs. 10-20 and 10-21). The focal nature of this necrosis-related atypia in an otherwise conventional giant cell tumor and the absence of atypical mitoses are helpful in avoiding a misdiagnosis of malignant change. In general, focal necrosis is a common finding in giant cell tumor and its presence is not indicative of aggressive behavior or malignant change.

Microscopic foci of aneurysmal bone cyst can be frequently documented if appropriate samples are available. The presence of such foci does not necessarily correlate with radiographic and gross features of a fully developed aneurysmal bone cyst. Typical radiographic and gross features of an expansile lesion with honeycombed blood-filled spaces can develop in some giant cell tumors (Figs. 10-8 and 10-9). A giant cell tumor is reported to be an underlying condition in 10% of secondary aneurysmal bone cysts. On the other hand, solid areas containing numerous multinucleated giant cells in a spindle-cell stroma are frequently present in an aneurysmal bone cyst and can be readily misinterpreted as an underlying giant cell tumor. This finding should be interpreted only with reference to appropriate radiographic features and clinical setting to avoid misdiagnosis of giant cell tumor.

In rare instances, florid proliferation of spindle cells that sometimes mimic so-called tissue culture fibroblastic proliferations can be present in giant cell tumors, further complicating the microscopic presentation of the lesion (Fig. 10-21). The overall similarity of these proliferations to nodular fasciitis is helpful to distinguish such benign reactive processes from sarcomatoid transformation.

Cytology

Fine needle aspirates of giant cell tumor typically show two populations of cells with predominating mononuclear cells and less abundant multinucleated giant cells (Fig. 10-22). Mononuclear cells, which show a histiocytoid appearance, are singly dispersed or may be arranged in small three-dimensional clusters (Fig. 10-22). Multinucleated giant cells are similar to osteoclasts but usually contain many more nuclei. Characteristically, the nuclei of mononuclear histiocytoid cells are identical to nuclei of giant osteoclast-like cells. This is a distinct cytologic feature of giant cell tumor of bone. The cytologic features of giant cell tumor of bone are often obscured by secondary changes, such as proliferation of fibrous tissue accompanied by foamy histiocytes. In such instances, correlation of cytologic findings with clinical and radiologic data may help to establish the correct diagnosis.

Giant cell reparative granuloma most frequently occurs in the jaws, where true giant cell tumors do not arise in the absence of underlying Paget’s disease. The most useful histologic criterion in making this distinction is the uniformity of distribution of the multinucleated giant cells and the absence of reactive bone formation and stromal collagenization in unaltered giant cell tumor. Brown tumor of hyperparathyroidism, which represents a giant cell reparative granuloma of known etiology, can be recognized by the characteristic biochemical findings of hypercalcemia, hypophosphatemia, and elevated parathormone levels. The absence of chondroid matrix and the characteristic plump, spindle-shaped appearance of the mononuclear cell component are important in excluding a giant cell–rich chondroblastoma or chondromyxoid fibroma. The exclusion of nonossifying fibroma should offer no substantial difficulty if attention is paid to radiologic signs of skeletal immaturity and metaphyseal location. Irregular distribution of compressed and attenuated multinucleated giant cells in a more fibroblastic background is also characteristic of nonossifying fibroma. Giant cell–rich osteosarcoma and malignant fibrous histiocytoma are differentiated on the basis of nuclear anaplasia, abnormal mitotic figures, and neoplastic osteoid production, which are present in the former. The summary of secondary changes complicating the cytoarchitectural features of conventional giant cell tumors and various clinical phenomena observed during its clinical course are summarized in Figure 10-23.

Approximately 25% of conventional giant cell tumors are considered to be locally aggressive on clinical or radiologic grounds.⁵ These tumors show extensive bone destruction, cortical expansion, and invasion into soft tissue.⁹³ These features cannot be correlated with any specific histologic findings. Approximately 25% to 35% of giant cell tumors recur after simple curettage.^{14,64–66,93} Recurrence typically occurs within 3 years of curettage.^64–66 In unusual instances, the lesion may recur many years or even decades after removal of the primary tumor. The recurrent lesion usually has the same morphologic features as the primary tumor (Fig. 10-24). Curettage supplemented by cryotherapy is used in some centers to reduce the rate of local recurrence. However, it is not universally accepted as a primary mode of treatment. Wide excision with allograft or prosthetic replacement significantly reduces, but does not completely eliminate, recurrences and is performed when appropriate and technically feasible.^14,15,65 The preferred mode of primary treatment of a conventional giant cell tumor is still thorough curettage and bone grafting.^14,15,65,96 This general approach is modified in relation to the anatomic site and clinical stage of the disease. Recurrent lesions are usually adequately treated by a second curettage. Recurrence in soft tissue is a rare local complication of a conventional giant cell tumor (Fig. 10-25). Typically, it is a result of tumor implantation into soft tissue at the time of surgical treatment.³⁰ It usually occurs within the first 3 years after surgical treatment of the primary lesion. In some unusual instances, it may occur many years after the removal of the primary tumor.^36,67 Recurrence can be identified on radiographs by a prominent shell of reactive bone surrounding its periphery (Fig. 10-25). Simple excision is usually sufficient to control the disease. In the past, radiation therapy was frequently used to control the disease locally and has been proved to be effective in preventing local recurrences. Because the majority of malignant transformations in giant cell tumor are linked to prior radiation, radiotherapy is no longer recommended as a primary mode of treatment.²¹ It is still, however, used to control the disease in anatomic sites, such as the spine, for which it is technically difficult to perform en bloc excision or complete curettage.^{2,17,96,100,103} Vasoocclusive therapy by arterial embolization may be considered as an alternative approach in anatomic sites for which it is technically difficult to remove the tumor mass surgically.¹⁹

Pulmonary metastases, or so-called benign pulmonary implants, may develop in approximately 1% to 2% of patients with conventional giant cell tumors. Typically the pulmonary nodules grow slowly and are amenable to surgical excision with a prospect for cure.^{10,11,24,25,51,62} Still, some patients may die of disease as a result of pulmonary miliary spread or progressive growth of multiple lung lesions.^21,24

In general, surgery is the main treatment modality for giant cell tumor and is occasionally complemented by radiation therapy.^{74,103,108,110,113} Recent advances in molecular biology of giant cell tumor has provided new treatment options, with the RANKL inhibitor (denosumab) and bisphosphonates, which inhibit osteoclast driven bone resorption.^{2,27,42,103,109,113} These two treatment options are most frequently used for primary tumors that cannot be resected or for metastatic disease that cannot be surgically controlled. The reported partial and complete responses to anti-RANKL therapy are causing an increased interest in this treatment modality.

Development of sarcoma in conventional giant cell tumor is the most serious complication but fortunately is rare. As mentioned previously, the majority of secondary sarcomas that arise in association with conventional giant cell tumor are linked to prior radiation therapy.^21,40 A primary (de novo) malignant giant cell tumor is a well-known but extremely unusual phenomenon. With the decline in the use of therapeutic irradiation for giant cell tumors, malignant transformation has become exceedingly rare.

Special Techniques

It appears that several cell types that belong to the macrophage/osteoclastic and osteoblastic lineages contribute to the development of giant cell tumors. Ultrastructurally, the cytoplasm of mononuclear cells contains abundant rough endoplasmic reticulum, moderate num­bers of mitochondria, a few lysosome-like bodies, and occasionally multiple lipid vacuoles.¹⁰⁵ The cytoplasm of the multinucleated giant cell contains numerous mitochondria, few lysosomes, and sparse, rough endoplasmic reticulum and appears to originate from mononuclear cells. Occasionally, filamentous viruslike intranuclear inclusions that are morphologically identical to those found in Paget’s disease of bone are present.^{1,22,32,68,98} Unlike the inclusions seen in the osteoclasts of Paget’s disease and in giant cell tumors that arise in a setting of Paget’s disease, these intranuclear inclusions can be found only after prolonged and careful survey of great numbers of cells. In summary, the ultrastructure is of little help to elucidate various dilemmas related to the origin of a giant cell tumor. It suggests, however, that the mononuclear cells have some ultrastructural similarities with cells of histiocytic lineage, macrophage lineage, or both. In fact, some of the mononuclear cells express the receptor for the immunoglobulin G crystallizable fragment and differentiation antigens associated with a macrophage-monocyte lineage.^13,52,57 Both mononuclear and multinucleated giant cells are also positive for α₁-antitrypsin.⁵⁷ The other major population of mononuclear cells in giant cell tumor does not express antigens of monocyte lineage, is strongly positive for tartrate-resistant acid phosphatase, and expresses parathormone and calcitonin receptors, indicating that the cells are undergoing osteoclastic differentiation (Fig. 10-26).^13,52 These cells also are functionally dependent on parathormone and calcitonin and increase their level of cyclic adenosine monophosphate on exposure to these hormones.^38,39,52 An intermediate population of mononuclear cells expressing phenotypic features of both monocyte-macrophage and osteoclastic lineages can also be found. The cells of monocyte-macrophage lineage do not proliferate well in vivo and are usually eliminated from tissue culture explants.³⁹ In contrast, the osteoclastic cells proliferate well in tissue culture, forming multinucleated giant cells. In summary, the main population of cells in giant cell tumor have phenotypic features of both macrophage-like and osteoclastic cells.^26,60 Recent cDNA microarray studies have identified that the TP63 gene encoding the p63 protein is ubiquitously overexpressed in giant cell tumor (approximately 70% of the cases) and can be used in the differential diagnosis of giant cell-containing lesions.⁵⁶ More recent investigations implicate that there is a subpopulation of stromal cells in giant cell tumors that are in fact osteoblastic in nature which have clonogenic potential and produce osteoclast differentiation signals.^{3,27,31,54,70,109,118} One of such signaling pathways involves a ligand for receptor activator of nuclear factor κB (RANKL).^4,45,54 In giant cell tumors, neoplastic stromal cells that express RANKL are thought to stimulate giant cell formation from the monocytic cells that express receptor activator of NFκB (Fig. 10-26).¹⁰⁹ The mechanisms of overexpression of RANKL by stromal cells are not well understood, but it is postulated that parathyroid hormone-related protein (PTHrP), also expressed by stromal cells in giant cell tumors, may play a role in the stimulation of RANKL.^20,73 PTHrP is in turn regulated by microRNA-126-5p, which has been shown to play a role as the upstream regulator in the PTHrP-RANKL axis.¹¹⁹ Surprisingly, mutations of the isocitrate dehydrogenase (IDH) genes, also frequently seen in gliomas, acute myeloid leukemias, and cartilaginous lesions, are often found in giant cell tumors.⁵⁰ The mutations involve the IDH2-R172S gene and can be documented in nearly 80% of giant cell tumors.⁵⁰ The mutations of the histone H3.3 encoding gene exclusively involving H3F3A and leading to a p.Gly34Trp change in the majority of cases were found in approximately 90% of giant cell tumors.⁷ Surprisingly, mutations of the histone H3.0 encoding gene were also found in a large proportion of chondroblastoma.⁷ Both of these mutations (i.e., those involving IDH2 and H2F3A) because of their high frequency, may represent driver mutations for giant cell tumor of bone but their exact biologic role in the development of this tumor is yet unknown.

Little is known about the factors governing local aggressive behavior, recurrence rate, and metastatic potential of conventional giant cell tumors. DNA ploidy measurements show that a high proportion of these lesions are aneuploid. This does not correlate with the clinical behavior of the lesion and cannot be used as a reliable factor for predicting recurrence or pulmonary metastases.^53,95,97 A majority of giant cell tumors show random or clonal chromosomal aberrations, with telomeric fusion being the most striking abnormality.^12,99 It has been suggested that this unique chromosomal aberration may correlate with aggressive local behavior, a high recurrence rate, or the metastatic potential of a conventional giant cell tumor.¹² This observation is based on analysis of a limited number of cases, and its true clinical value remains to be elucidated. Allelic losses of 1p, 9q, and 19q are frequent in giant cell tumors but do not correlate with local recurrence or metastatic potential.⁸³ In contrast, loss of genetic material on 17p in proximity to the p53 locus and on 9p appear to correlate with the metastatic potential of giant cell tumors.⁸³ This observation is in concert with the identification of TP53 mutations and deletions that parallel the malignant transformation of giant cell tumors.^76,77,92 The pathways that may play a role in the aggressive behavior of giant cell tumors include the upregulation of p53 signaling, osteoclast differentiation, and Wnt signaling. Among these pathways the upregulation of IGF1, MDM2, STAT1, and RAC1 appear to be most significantly associated with a recurrence, while genomic amplifications involving CCND1 and MET were found in association with malignant transformation.^18,91 Similar to many other tumors, giant cell tumor of bone, both primary and metastatic, may ectopically upregulate beta-human chorionic gonadotropin.⁵⁵

Personal Comments

Giant cell lesions in bone are the most frequently encountered diagnostic problems in consultation material. The ubiquitous distribution of multinucleated giant cells of osteoclastic type accounts for this morphologic overlap and for difficulties in segregating true giant cell tumors from unrelated giant cell–containing lesions. The key to distinguishing these lesions is in the unswerving adherence to clinicoradiologic correlation to arrive at a diagnosis.

Generally, a diagnosis of giant cell tumor is suggested by the presence of a radiolucent lesion in the end of a long bone or an equivalent epiphyseal site in a skeletally mature individual. Other common locations include the sacrum and “epiphyseoid” bones, such as the carpal and tarsal bones and the patella. The true giant cell tumor, for practical purposes, does not arise in the craniofacial skeleton, and it very rarely develops in nonepiphyseal locations. The short tubular bones of the hands and feet present a particular problem because of the morphologic overlap with giant cell reparative granuloma, which has a predilection for this skeletal site. In this situation, attention to the specific site of involvement with respect to epiphyseal location and skeletal maturity is particularly important. Perhaps the most important problem in histologic recognition of true giant cell tumor is created by the tendency for this tumor to undergo fibrohistiocytic reactive changes that can simulate benign or malignant primary tumors of fibrohistiocytic origin. Such changes can largely or even completely obscure the classic histologic appearance of giant cell tumor. It is this tendency that has led to the misapplication of the term benign or malignant fibrous histiocytoma of bone to some examples of altered giant cell tumor. Strict adherence to the use of clinicoradiologic correlation and thorough sampling of the tumor tissue avoid most of these errors in diagnosis.

Another question that frequently arises is the extent to which the aggressiveness of a giant cell tumor can be predicted on the basis of histologic criteria. Whether to assign numeric grades or to use adjectival modifiers in designating local aggressiveness or metastasizing potential has been debated extensively. Our experience indicates that the use of such devices is without merit, except to designate giant cell tumor as conventional or malignant (either primary or secondary) on the basis of the presence or absence of frankly sarcomatous features.