Giant cell tumor of bone

Last revised by Keshaw Kumar on 13 Oct 2023

Giant cell tumors (GCT) of bone are locally aggressive and rarely malignant or metastasizing bony neoplasms, typically found at the end of long bones which is the region around the closed growth plate extending into the epiphysis and to the joint surface 1. They are classified as osteoclastic giant cell-rich bone tumors of uncertain behavior 1.

GCT accounts for the 'G' in the popular mnemonic for lucent bone lesions FEGNOMASHIC.

Giant cell tumors of bone are also known as osteoclastomas or benign fibrous histiocytomas but those terms are no longer recommended 1

Giant cell tumors are rare with an estimated incidence of 1.2-1.7 per million person-years making up for 4-5% of all primary bone neoplasms and about 20% of all benign bone tumors 1-4.

They almost invariably (97-99%) occur when the growth plate has closed and are therefore typically seen in early adulthood. 80% of cases are reported between the ages of 20 and 50, with a peak incidence between 20 and 30 4,5. There is overall a mild female predilection, especially when located in the spine.

Malignant transformation occurs in <10% 2 and is apparently more common in men (M:F ~3:1) 5.

Some multicentric giant cell tumors have been found in association with the following syndromes 1,6:  

The definitive diagnosis of giant cell tumor of bone is based on a combination of typical radiological and pathological features.

Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 1:

  • circumscribed osteolytic bone tumor involving the epiphysis

  • usual occurrence in a skeletally mature person

  • histological evidence of numerous non-neoplastic osteoclastic giant cells and fewer neoplastic mononuclear cells usually without atypia

The following molecular criterium is desirable:

  • cells with H3.3 p.Gly34 mutation

Often they are incidentally identified. They may present insidiously with pain and swelling or symptoms related to compression of adjacent structures. If the spine is affected they can present with symptoms related to nerve root compression 1. A pathological fracture may result in an acute presentation.

Complications include 1:

Giant cell tumors are locally aggressive and rarely metastasizing neoplasms often found eccentrically located at the end of long bones affecting the metaphysis and epiphysis 1. The origin is thought to be the metaphyseal side of the growth plate since rare tumors in skeletally immature patients are found in a metadiaphysial location and the growth plate and the open growth plate present a barrier to tumor growth 5. They consist of neoplastic mononuclear stromal cells and numerous non-neoplastic osteoclast-like giant cells. This is believed to result from an over-expression in the RANK/RANKL by neoplastic mononuclear stromal cells signaling pathway with resultant hyperproliferation of osteoclasts 7-9.

Giant cell tumors are locally aggressive tumors. Malignant giant cell tumors are rare. Secondary malignant transformation can occur after treatment and is more common than the primary malignant variants 1.

The etiology of the majority of giant cell tumors, that occur sporadically, is unknown 1.

The ones that can be associated with pheochromocytoma-paraganglioma and giant cell tumor syndrome are caused by an early H3.3 mutation 1.

They typically occur in an eccentric position at the end of long bones in the mature skeleton with involvement of the subarticular regions. The most commonly affected bones/locations are 1,4:

  • distal femur and proximal tibia: 50-65%

  • distal radius: 10-12%

  • proximal humerus: 4-8%

  • sacrum: 4-9%

  • vertebral bodies: 3-6% (thoracic spine most common, followed by cervical and lumbar spines)

Less frequently they occur in other locations including hands and feet and the innominate bones of the pelvis 1,4.

Occasionally they occur in the metaphysis.

Multiple locations are rare and most often involve the extremities 1.

Giant cell tumors of bone can be classified into the following subtypes 1:

  • conventional giant cell tumor of bone

  • malignant giant cell tumor of bone

Macroscopically, giant cell tumors of bone are variable in appearance with soft friable red-tannish hemorrhagic areas of blood-filled cystic spaces admixed with cream-yellow and firm whitish colored areas corresponding to xanthomatous changes and fibrous tissue 1.

Other features include the following 1:

  • eccentric position within long bones

  • thinning or partial destruction of the surrounding cortex

  • generally contained periosteum

  • possible erosion of the subchondral bone plate but only rare extension into the joint space

Histologically giant cell tumors of bone are characterized by the following 1:

  • multiple non-neoplastic osteoclastic giant cells with neoplastic mononuclear cells in between

  • osteoclastic giant cells with a variable number of nuclei

  • mononuclear cells with variable morphology

  • numerous mitoses

  • atypical mitoses suggest malignancy

  • hemorrhage, aneurysmatic change, foamy macrophages and hemosiderin deposition occur

  • necrosis can be present, especially in the setting of a pathologic fracture

  • cortical bone erosion or destruction with reactive new bone formation in the tumor periphery

  • usually contained by periosteum without soft tissue invasion

The malignant tumor components do not display any specific features and can resemble those of undifferentiated sarcoma, fibrosarcoma or osteosarcoma 1.

It is important to realize that features may be difficult to interpret histologically with a relatively wide histological differential diagnosis (e.g. giant cell reparative granuloma, brown tumor, osteoblastoma, chondroblastoma, non-ossifying fibroma, and even osteosarcoma with abundant giant cells) 5, thus rendering radiology indispensable to the interpretation of these lesions.

On immunohistochemistry, H3.3-G34W is considered a reliable marker 1,9,10.

Giant cell tumors of bone show pathogenic H3-3A(H3F3A) of which ~90% are H3.3 p.Gly34Trp and less common H3.3 p.Gly34Leu 1,9.

The characteristic radiographic appearance of a giant cell tumor located in a long bone includes 4,5,8:

  • osteolytic or radiolucent lesion

  • well-defined non-sclerotic margin (though <5% may show some sclerosis)

  • eccentric location (maybe difficult to assess if the lesion is large)

  • extension to the subchondral bone (in 84-99% within 1 cm of the articular surface 5)

  • closed growth plates

General radiographic features 5:

  • a narrow zone of transition: a broader zone of transition is seen in more aggressive giant cell tumors

  • usually no surrounding sclerosis (80-85%)

  • cortical thinning, expansile remodeling, cortical breakthrough

  • frequent trabeculation

  • no matrix mineralization

  • a pathological fracture may be present

  • a periosteal reaction might be seen

Peripheral new bone formation with cortical bone reconstitution might be seen in denosumab-treated tumors 1.

On CT giant cell tumors of bone are usually depicted as eccentrically located solitary lucent bone lesions.

The absence of matrix mineralization, cystic changes and aggressive features such as cortical involvement/thinning, pathological fractures, aggressive periosteal reaction and soft tissue extension can be better delineated than on plain radiographs 5,8.

MRI imaging findings are nonspecific. Features that can be demonstrated on MRI include:

  • T1

    • low to intermediate signal (solid component)

    • low signal rim

  • T2: heterogeneous high signal with areas of low signal intensity due to hemosiderin or fibrosis 12

  • T1 C+ (Gd): solid components will enhance

Enhancing solid components can help to distinguish giant cell tumors of bone with hemorrhagic areas and aneurysmal bone cyst-like changes from a pure aneurysmal bone cyst.

Giant cell tumor of bone with a positive response on denosumab should show the following characteristics 9:

  • reduction in tumor size

  • lower signal intensity on both T1 and T2 weighted images

  • shrinkage of cystic tumor components

On bone scintigraphy, most giant cell tumors demonstrate increased uptake on delayed images, especially around the periphery, with a central photopenia (doughnut sign) 1. Increased blood pool activity is also seen, and can be seen in adjacent bones due to generalized regional hyperemia (contiguous bone activity).

  • intense 18-F FDG uptake 20

Angiography is only rarely performed e.g. in the setting of preoperative embolization. Tumors are usually hypervascular (two-thirds of cases) with the rest being hypovascular or avascular 5.

The radiological report should include a description of the following 9,11:

  • location and size

  • tumor margins and transition zone

  • relation to the growth plate and articular surface

  • cystic and solid tumor components

  • fluid-fluid levels suggesting aneurysmal bone cyst-like changes

  • concerning features

    • cortical involvement

    • soft tissue extension

    • pathologic fracture

    • aggressive periosteal reaction

    • surrounding bone marrow edema

    • solid mass-like enhancement

    • associated joint effusion

  • risk factors for local recurrence 9

    • soft tissue extension (see above)

    • distance from the articular surface (<2 mm)

    • the thickness of the unaffected cortical bone around the tumor (<3 mm)

On CT and MRI the lesion can be categorized as Bone-RADS 4 unless histology has been already obtained 11.

Classically treatment is with curettage usually combined with local adjuvants such as polymethylmethacrylate (PMMA), phenol or liquid nitrogen or a combination of those 8. Local recurrence is common and occurs in 15-50% of conventional giant cell tumors of bone within 2 years depending on the type of surgical treatment and on the presence of soft tissue extension 1,8. En bloc resection is associated with a lower recurrence rate but with greater morbidity. The newer intraoperative adjuncts such as thermocoagulation, cryotherapy, or chemical treatment of the resection margins have lowered the recurrence rate to an acceptable level 5.

About 3-7% of patients with conventional giant cell tumor of bone develop pulmonary metastases with a median interval of about 15 months from the local recurrence 1. They seem to have a good prognosis 13,14.

Denosumab has been used in the treatment of benign metastasizing disease, in unresectable tumors and in patients where surgery is likely to cause excessive morbidity as well as neoadjuvant therapy to facilitate surgery in locally advanced tumors 1.

Giant cell tumors of bone were first described by the English surgeons Astley Paston Cooper and Benjamin Travers in 1818 4,15 and later characterized by the American pathologists Henry Louis JaffeLouis Lichtenstein and R B Portis in 1940 16

There is a relatively wide differential similar to that of a lytic bone lesion:

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