AUTHOR INFORMATION	Section 1 of 10
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Author: Lesley-Ann Goh, MBBS, FRCR, Registrar, Department of Diagnostic Radiology, Tan Tock Seng Hospital Coauthor(s): Wilfred CG Peh, MBBS, MD, FRCPE, FRCPG, FRCR, Clinical Professor, Faculty of Medicine, National University of Singapore; Senior Consultant Radiologist, Programme Office, Singapore Health Services; Tony WH Shek, MBBS, FRCPA, Honorary Clinical Assistant Professor, Department of Pathology, University of Hong Kong

Editor(s): Giuseppe Guglielmi, MD, Assistant Professor, Department of Radiology, Scientific Institute Hospital; Bernard D Coombs, MBChB, PhD, Assistant Professor, Department of Radiology, University of Colorado Health Sciences Center; Murali Sundaram, MBBS, FRCR, Department of Radiology, Mayo Clinic of Rochester; Robert M Krasny, MD, Visiting Assistant Professor of Radiology, University of California at Los Angeles Medical Center; Consulting Staff, Tower Imaging, Los Angeles, California; and Felix S Chew, MD, EdM, Vice-Chair for Education, Section Head of Musculoskeletal Radiology, Professor, Department of Radiology, Wake Forest University School of Medicine

	INTRODUCTION	Section 2 of 10
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Background: Giant cell tumour of the bone is a relatively uncommon tumour. It is characterized by the presence of multinucleated giant cells. The tumour is usually regarded as benign. In most patients, giant cell tumors have an indolent course, but tumors recur locally in as many as 50% of cases. Metastasis to the lungs may occur.

Cooper first reported giant cell tumors in the 18th century. In 1940, Jaffe and Lichtenstein defined giant cell tumour more strictly to distinguish it from other tumors. Giant cell tumour usually occurs de novo but also may occur as a rare complication of Paget disease of the bone.

Pathophysiology: Giant cell tumour of the bone has a distinctive microscopic appearance, and its diagnosis usually is not difficult, though the gross appearance of a giant cell tumour is less characteristic. The tumour is usually seen as a soft, brown mass. Areas of haemorrhage, which appear dark red, and areas of collagen, which appear gray, may be observed.

On cut sections, necrosis and blood-filled spaces are commonly seen. Intact resected specimens of giant cell tumor are uncommon because most patients are treated by curettage. Grossly, the curettage material is soft, friable, and dark brown. Although called giant cell tumor, the basic proliferating cell is the background mononuclear stromal cell in which the characteristic osteoclastlike giant cells are uniformly distributed (see Image 1). The origin of the mononuclear cells is not fully known, but they are believed to be derived from primitive mesenchymal stem cells or cells of a histiocytic macrophage origin.

Osteoclastlike giant cells have an identical nuclear morphology, which is presumably formed by the fusion of mononuclear stromal cells. Mononuclear cells commonly have a round or ovoid nucleus, but occasionally, they can be spindle shaped. They possess a variable amount of eosinophilic cytoplasm. No intercellular matrix is produced by the mononuclear or multinucleated giant cells. Mitotic activity is highly variable and of no prognostic significance. Similarly, the grade of a giant cell tumor of the bone has no prognostic significance.

Although a typical giant cell tumor of the bone is easy to diagnose, a few histologic variants are not uncommon. Small foci of aneurysmal bone cysts are common in giant cell tumor (see Image 2). In rare circumstances, these foci may dominant the histologic features. Hence, thorough sampling for an underlying giant cell tumor is indicated. Occasionally, a giant cell tumor is composed predominantly of spindle cells and foam cells to the extent that no discernible osteoclastlike giant cells are found. Such tumors can easily be mistaken for benign fibrous histiocytoma or xanthoma (see Image 3). Again, if the clinical and radiologic impressions suggest a giant cell tumor, thorough tissue sampling of areas in which giant cell tumor typically occur is warranted; usually, a minute residual focus of giant cell tumor is found.

Although giant cell tumor forms no intercellular matrix, foci of reactive bone formation can be seen, especially in tumors complicated by fracture. Areas of infarct are not uncommon in giant cell tumors. Intravascular tumor emboli may be found in the periphery of some giant cell tumors, but this finding does not appear to be correlated with its metastatic potential. Occasionally, an otherwise typical giant cell tumor of the bone can metastasize, usually to the lungs (see Image 4). Surprisingly, metastatic giant cell tumor does have an ominous prognosis, and patients can expect long-term survival after the metastases are surgically excised.

Note that multinucleated osteoclastlike giant cells are not pathognomonic of giant cell tumor of the bone. Osteoclastlike giant cells can be found in a wide variety of normal, reactive, benign, and malignant neoplastic conditions. Brown tumor in hyperparathyroid bone disease is an important nonneoplastic mimic of giant cell tumors. The 2 can be histologically identical, but they have different clinical presentations and radiologic appearances. Hyperparathyroid bone disease is a generalized metabolic disease with increased serum calcium levels, whereas giant cell tumor is a localized disease.

Giant cell reparative granuloma is a benign reparative lesion that affects the small bones of the hands and feet. It has considerable histologic similarity to giant cell tumors of the bone. Other primary bone tumors that contain osteoclastlike giant cells include chondroblastoma, chondromyxoid fibroma, and giant cell osteosarcoma.

Frequency:

Internationally: Giant cell tumor of the bone accounts fro 4-5% of primary bone tumors and 18.2% of benign bone tumors. The incidence is increased in patients with Paget disease of the bone, in which giant cell tumor is a rare neoplastic complication. Giant cell tumor is a rare complication compared with Paget sarcoma, which has an incidence of sarcomatous change of <5%.

Mortality/Morbidity:

Giant cell tumors are commonly benign.

However, in 5-10% of patients, the tumors are malignant.

The malignant tumors usually result from secondary malignant transformation after radiation treatment.

Race:

All races are affected.

A higher incidence is noted in the Chinese persons, in whom the incidence is approximately 20% among those with primary bone tumors. This percentage is higher than the estimated 4-5% incidence in western studies.

Sex: A slight female predominance is noted; approximately 50-57% of cases involve female patients.

Age: Typically, giant cell tumors occur in skeletally mature patients aged 20-40 years. The incidence peaks in those aged 20-30 years.

Giant cell tumors are much less common in children; the rate is 5.7% in skeletally immature patients.

Vertebral tumors tend to occur in younger patients; 29% of these tumors occur in those aged 0-20 years.

Multicentric giant cell tumors also occur in a younger group, with a peak incidence in those aged 10-20 years. Multicentric tumors involve fewer than 1% of patients.

Anatomy: Most giant cell tumors (60%) occur in the long bones, and almost all of the tumors are located at the articular end of the bone (see Image 5). Metaphyseal involvement may occur in skeletally immature patients. Common sites include the proximal tibia, distal femur, distal radius, and proximal humerus, although giant cell tumors have also been reported to occur in the pubic bone, calcaneus, and feet.

Giant cell tumors also may occur in the vertebrae (see Image 6). Giant cell tumors are 3-4 times as common in the sacrum as they are in the rest of the spine. Sacral tumors may be so extensive that they involve the entire sacrum. Rarely, the tumor may extend across the sacroiliac joint to involve the adjacent ilium or extend across the L5-S1 disk to involve the posterior elements of L5 vertebra. The location of giant cell tumors within the spine can vary and most commonly involve the vertebral body, followed by the vertebral arch. The rib is an additional rare site of giant cell tumors (see Image 7).

Clinical Details: Giant cell tumors typically occur in adults aged 20-40 years. Patients often complain of pain and swelling at the affected site. Pathologic fracture is present in 10% of patients (see Image 8). Vertebral giant cell tumors may extend into the spinal canal and compress the spinal cord, resulting in neurologic symptoms. Giant cell tumors are rarely multicentric (see Image 9). This condition should be considered when patients present with giant cell tumors in the hands, because the incidence of tumors in the small bones of the hand and sacrum is increased.

Preferred Examination: The radiographic appearance of giant cell tumors is often characteristic.

MRI is sensitive for the detection of soft tissue changes, intra-articular extension, and marrow changes. MRI is the best method for assessing subchondral breakthrough and extension of tumor into the adjacent joint. Its diagnostic accuracy is high, especially when MRIs are interpreted in conjunction with plain radiographs.

CT scans and bone scans are usually less useful than the other examinations.

Limitations of Techniques: On radiographs, typical giant cell tumors are usually easily distinguished from other bone tumors. Giant cell tumors are lytic and subarticular and eccentric; they often lack a sclerotic rim. However, unusual variants may make the radiographic diagnosis difficult.

The disadvantages of MRI include its relatively high cost and limited availability. Some patients experience claustrophobia during the examination and may require sedation. MRI also is contraindicated in patients with cardiac pacemakers, orbital foreign bodies, and noncompatible aneurysmal clips.

	DIFFERENTIALS	Section 3 of 10
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Aneurysmal Bone Cyst
Chondroblastoma
Hyperparathyroidism, Primary

Other Problems to be Considered:

Telangiectatic or fibrogenic variants of osteosarcoma
Malignant fibrous histiocytoma (bone)
Metastasis
Plasmacytoma

	X-RAY	Section 4 of 10
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Findings: The most important radiographic findings of giant cell tumor include the location of the tumor, its lytic nature, and the lack of a host response.

Typically, giant cell tumors are expansile, osteolytic, radiolucent lesions without sclerotic margins and usually without a periosteal reaction. Septa may be seen in the lesion in 33-57% of patients (see Image 10); these represent nonuniform growth of the tumor rather than true septa. The tumors are typically large when they are discovered, with lesion diameters mostly in the range of 5-7 cm.

Most giant cell tumors (85%) occur in the long bones; approximately 50% are located in the bones around the knee. The location is important in the diagnosis of giant cell tumor. Most tumors are eccentric and are seen in a subarticular location (see Image 11). However, the tumor originates in the metaphysis, and the common epiphyseal involvement is the result of the patient’s age at presentation (mature skeletons). Early lesions may lie solely in the metaphysis. A narrow zone of transition with a lack of sclerosis at its margins is a distinctive finding and strongly suggestive of the diagnosis. Sclerosis of the tumor margins, occasionally present, is seldom complete. Periosteal reactions are usually not seen; the lack of host reactive response is typical of giant cell tumors.

Giant cell tumors in the spine are uncommon and account for only 5% of giant cell tumors. The sacrum is the most common location. Patients with these tumors tend to be slightly younger than those with tumors in the appendicular skeleton. The location in the vertebrae can vary, but the tumor more commonly involves the vertebral body. On radiographs, the tumors may be seen areas of destruction in the vertebral body with invasion of the posterior elements. The tumor can cause vertebral collapse and spinal cord compression, especially when it involves the posterior elements.

Degree of Confidence: The degree of confidence is high for radiography in the appendicular skeleton. In the spine, the degree of diagnostic confidence is not high, and giant cell tumors usually cannot be differentiated from other types of tumors. Tumors in the sacrum are recognizable, and these may be diagnosed on the basis of their appearance and location.

False Positives/Negatives: Unusual forms of certain tumors may mimic giant cell tumors.

Telangiectatic or fibrogenic variants of osteosarcoma may not produce visible ossifications or calcifications. These variants may be eccentric, and the tumors may extend to the subarticular surface, mimicking a giant cell tumor.

Malignant fibrous histiocytomas occur in a similar age group, and these can also mimic a giant cell tumor.

Brown tumors of hyperparathyroidism are a well-known differential diagnosis of giant cell tumors.

Chondroblastomas may be mistaken for giant cell tumors because of their subarticular location. However, careful review of the radiograph usually reveals that the epicenter lies in the epiphysis rather than in the metaphysis. The presence of chondroid calcifications further supports the diagnosis of chondroblastoma.

Aneurysmal bone cysts may be only slightly expansile in the early stages, and they can extend to the subarticular cortex, mimicking a giant cell tumor. These cysts usually occur in younger patients. Approximately 29% of aneurysmal bone cysts are reported to be associated with some other solid bone lesion, 39% of which are giant cell tumors.

	AUTHOR INFORMATION	Section 1 of 8
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Author: James R Verheyden, MD, Fellow in Hand Surgery, Department of Orthopedics and Sports Medicine, University of Washington Coauthor(s): Timothy Damron, MD, Associate Professor, Department of Orthopedics, Division of Orthopedic Oncology - Joint Reconstructive Surgery, State University of New York at Syracuse, Upstate Medical University

James R Verheyden, MD, is a member of the following medical societies: American Academy of Orthopaedic Surgeons

Editor(s): Timothy Damron, MD, Associate Professor, Department of Orthopedics, Division of Orthopedic Oncology - Joint Reconstructive Surgery, State University of New York at Syracuse, Upstate Medical University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Sean P Scully, MD, PhD, Senior Associate Consultant, Department of Orthopedics, Mayo Clinic of Rochester; Dinesh Patel, MD, Assistant Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital; and Harris Gellman, MD, Clinical Professor of Orthopedic Surgery, University of Arkansas and University of Miami; Consulting Surgeon, Broward Hand Center

	INTRODUCTION	Section 2 of 8
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Giant cell tumors of the tendon sheath are the second most common tumors of the hand, with simple ganglion cysts being the most common. Chassaignac first described these benign soft-tissue masses in 1852, and he overstated their biologic potential in referring to them as cancers of the tendon sheath.

Giant cell tumors of the soft tissue are classified into the common localized type and the rare diffuse type. The rare diffuse form is considered the soft tissue counterpart of diffuse pigmented villonodular synovitis (PVNS). The diffuse form typically affects the lower extremities. Its anatomic distribution parallels that of PVNS, with lesions most commonly found around the knee, followed by the ankle and foot. However, the diffuse form occasionally affects the hand. Typically, these lesions, like those of PVNS, occur in young patients; the condition is diagnosed in one half of the patients before they are aged 40 years. The diffuse form is often locally aggressive, and multiple recurrences after their excision are common.

Because of the similarity in patients’ ages, tumoral locations, clinical presentations, and symptoms in PVNS and the diffuse form of giant cell tumors of the tendon sheath, the diffuse form probably represents an extra-articular extension of a primary intra-articular PVNS process. Findings from flow cytometric DNA analysis suggest that PVNS and giant cell tumors of the tendon sheath are histopathologically similar but clinically distinct lesions. When the origin of these poorly confined soft-tissue masses is uncertain, Enzinger and Weiss classify these tumors as the diffuse type of giant cell tumors of the tendon sheath, whether or not they involve the adjacent joint.

This article focuses on the common localized form of giant cell tumors, that is, the giant cell tumors of the tendon sheath that often are found in the hands and feet.

History of the Procedure: Giant cell tumors of the tendon sheath are usually painless masses that have been present for a long time. The reported duration of symptoms ranges from weeks as long as 30 years. These tumors usually cause no symptoms, except for occasional distal numbness. However, mild disability may result from impaired function of the digit secondary to the size of the lesion.

Frequency: Giant cell tumors of the tendon sheath are the second most common tumors in the hand; simple ganglion cysts are the most common. Giant cell tumors of the tendon sheath most commonly occur in patients aged 30-50 years, with a peak incidence in those aged 40-50 years. Rarely are these tumors found in patients younger than 10 years or in patients older than 60 years. The female-to-male ratio is 3:2 female.

Giant cell tumors of the tendon sheath are associated with degenerative joint disease, especially in the distal interphalangeal (DIP) joint. Jones et al noted degenerative joint disease in the joint from which a tumor arose or in the joint nearest to the mass in 46 of 91 cases in which radiographs were reviewed. An occasional association with rheumatoid arthritis has been reported. However, to the authors’ knowledge, no pathogenetic relationship between rheumatoid arthritis and giant cell tumor of the tendon sheath has been demonstrated, and their simultaneous occurrence may be coincidental. Antecedent trauma occurs in a variable number of these patients, but its association is also probably coincidental.

Etiology: As is true for most soft tissue tumors, the etiology of giant cell tumors of the tendon sheath is unknown. Theories of their pathogenesis have included trauma, disturbed lipid metabolism, osteoclastic proliferation, infection, vascular disturbances, immune mechanisms, inflammation, neoplasia, and metabolic disturbances. Probably the most widely accepted theory, as Jaffe et al proposed, is that of a reactive or regenerative hyperplasia associated with an inflammatory process.

Histochemical evidence shows that the mononuclear cells and giant cells present in these lesions resemble osteoclasts, suggesting a bone marrow–derived monocyte/macrophage lineage for these tumors. Recent polymerase chain reaction (PCR) assays have shown that giant cell tumors of the tendon sheath are polyclonal proliferations. This evidence suggests that these masses are nonneoplastic proliferations, if one accepts the premise that a population of cells forming a tumorous mass must show clonality to be classified as a neoplasm.

Clinical: Typically, these masses occur along the volar aspect of the hand and fingers and are most commonly adjacent to the DIP joint. Two thirds of these masses are located along the volar aspect of the fingers (see Image 1). The index and long fingers most commonly involved. Despite the prevalence of volar lesions, a dorsal location is not uncommon. A slight predominance for the right hand exists. The second most common site is the toe. Less common sites include extra-articular areas around larger joints, such as the knees, wrists, and ankles.

Giant cell tumors of the tendon sheath are firm, lobulated, nontender, slow-growing masses that are firmly fixed to the underlying structures. Usually, the overlying skin is freely mobile over proximal masses in the fingers; more commonly, the skin is adherent to distal tumors. In digital lesions, mild numbness in the distal part of the involved fingertip is occasionally present. The lesion is not transilluminating. (Transillumination is more consistent with a cystic structure.)

The clinical differential diagnosis may include foreign body granuloma, necrobiotic granuloma, tendinous xanthoma, fibroma of the tendon sheath, infection, ganglion cyst, rheumatoid nodule, epidermoid cyst, lipoma, and a knuckle pad, among other less common entities. Many of these entities can often be excluded with careful history taking and physical examination.

When the pressure of the mass causes cortical erosion or when the mass has intralesional calcification, the radiographic differential diagnosis includes synovial chondromatosis, calcific tendonitis, and periosteal chondroma. Other entities that cannot be excluded on the basis of clinical findings in many cases include fibrokeratoma, myxoid cyst, reticulohistiocytoma, metastasis, and soft tissue sarcomas (particularly epithelioid sarcoma and synovial sarcoma); these entities can be definitively distinguished only by means of histologic review.

	RELEVANT ANATOMY AND CONTRAINDICATIONS	Section 3 of 8
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Relevant Anatomy: See Histologic Findings.

Contraindications: A patient’s poor medical health and the presence of life-threatening illnesses are contraindications to the surgical resection of these tumors.

	WORKUP	Section 4 of 8
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Imaging Studies:

Plain radiography

Plain radiographs demonstrate a benign-appearing circumscribed soft-tissue shadow in 50% of cases. These radiographs also show cortical erosion of the bone due to a pressure effect of the adjacent mass on the cortex in 10-20% of cases (see Images 2-3).