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.
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Terminology
Giant cell tumors of bone are also known as osteoclastomas or benign fibrous histiocytomas but those terms are no longer recommended 1.
Epidemiology
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.
Associations
Some multicentric giant cell tumors have been found in association with the following syndromes 1,6:
pheochromocytoma-paraganglioma and giant cell tumor syndrome
Diagnosis
The definitive diagnosis of giant cell tumor of bone is based on a combination of typical radiological and pathological features.
Diagnostic criteria
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
Clinical presentation
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
Complications include 1:
tumor recurrence
nerve root compression in vertebral location
Pathology
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.
Etiology
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.
Location
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:
the 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.
Subtypes
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
Macroscopic appearance
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
Microscopic appearance
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.
Immunophenotype
On immunohistochemistry, H3.3-G34W is considered a reliable marker 1,9,10.
Genetics
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.
Radiographic features
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
Plain radiograph
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.
CT
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
MRI imaging findings are nonspecific. Features that can be demonstrated on MRI include:
hemorrhagic areas
fluid-fluid levels suggesting aneurysmal bone cyst-like changes 1
surrounding bone marrow edema
soft tissue extension
solid tissue components
Signal characteristics
-
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
Nuclear medicine
Bone scintigraphy
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).
Angiography (DSA)
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.
Radiology report
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.
Treatment and prognosis
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.
History and etymology
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 Jaffe, Louis Lichtenstein and R B Portis in 1940 16.
Differential diagnosis
There is a relatively wide differential similar to that of a lytic bone lesion:
chondroblastoma: epiphyseal, usually in skeletally immature patients
chondromyxoid fibroma: metaphyseal, with a well defined sclerotic margin, multiloculated bubbly appearance 17
aneurysmal bone cyst (ABC): younger age group, but may co-exist with giant cell tumor; fluid-fluid levels
non-ossifying fibroma: usually younger age group 5
brown tumor: in the setting of hyperparathyroidism
enchondroma: only really a consideration in lesions of small bones of the hand and foot 3
chondrosarcoma: typically older age group
undifferentiated sarcoma of bone
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