Giant cell tumor (GCT) is one of the most common benign bone tumors, which occurs in young adults 20-40 years old with a high recurrence rate and a potential for aggressive behavior.[1] It is most commonly located at the metaphyseal or epiphyseal portion of the tibia or femur. While overall GCT has a benign characteristic, the disease behavior spectrum is extremely unpredictable. Local aggressiveness can range from focal symptoms due to bony or cortical destruction, up to surrounding soft tissue expansion and metastasis. An occurrence within the axial skeleton can lead to severe local complications and is usually unresectable.[2]
The biopsied tissue have multinucleated giant cells under the microscope. They consist of three different cell types:
The tumor bone resorption is primarily done by the giant cells. The spindle-like stromal cells recruit monocytes and promote their fusion into giant cells. The stromal cells also improve the resorptive ability of the giant cells.
The exact etiology of GCT is not fully understood yet. It remains uncertain whether it is a true neoplasm or just a reactive condition. A 20q11 amplification is seen in 54% of GCTs, over-expression of p53 in 20% of them. Centrosome amplification, and boosted telomerase activity with the prevention of telomeres shortening support a neoplastic etiology.[4][5][6]
Giant cell tumors of the bone represent 4-10% of all primary bone tumors and 15-20% of all benign bone tumors.[7] It mostly affects young adults. Approximately half of the tumors occur in adults in their third and fourth decades of life. It is rarely seen in patients older than 50 years. GCTs have a female-to-male ratio of between 1.3 and 1.5 to 1. It has a significantly higher incidence among Asians compared with western populations. Of the reported lesions, 44% have been described around the knee joint, 10% in the distal radius, 6% in the proximal humerus, and 13% in hands and feet. Spine and skull are rarely affected. The mandible and maxilla as the more favored sites in the head.
Although benign, these tumors exhibit locally aggressive behavior and own the potential to metastasize. Around 1 to 5% of cases show metastasis and there is a positive correlation between the occurrence of metastases and local aggressiveness and recurrence.[8] Metastases most frequently occur in the lungs.[9] Varying degrees of local aggressiveness, like a simple cortical breakthrough, extension into surrounding soft tissues, and articular structures can cause severe and debilitating local complications. The risk of recurrence is approximately 35%.[10]
The rumor is sporadic before the age of 20, with less than 5% of the tumors occurring in skeletally immature patients.[11] A higher incidence of vertebral GCT and multicentricity is noted in patients with skeletal immaturity. In contrast to solitary, the multifocal lesions are rarer but more aggressive.[12] Patients with Paget's disease show an increased incidence of GCT in which flat bones like the skull and pelvis are more commonly involved.[13]
The receptor activator of nuclear factor kappa B [NF-kB] ligand (RANKL) appears to be critical to the pathogenesis of GCT. Under normal physiologic conditions, osteoclast formation requires interaction with cells of the osteoblastic lineage, which may depend upon cell-cell contact, and the interaction of RANKL with its receptor RANK.[14] This receptor is highly expressed on monocytes, while RANKL is expressed by a variety of cell types, including stromal cells and lymphocytes. A variety of co-regulatory molecules also take part in osteoclast formation, including monocyte-colony-stimulating factor, vitamin D, parathyroid hormone and parathyroid hormone-related protein, and prostaglandins.[15]
Several studies identified RANKL as highly expressed by the stromal cells within a GCT.[15][16] The stromal cells also secrete factors that can regulate or prevent osteoclastogenesis, including osteoprotegerin, which blocks osteoclast/osteoblast interactions and functions as a natural negative regulator of RANKL.[17] The expression of RANKL by the osteoblast-like mononuclear stromal cells stimulates the recruitment of the osteoclastic cells from a normal monocytic pre-osteoclast cell. The osteoclastic giant cells then actively absorb host bone via a cathepsin K and matrix metalloproteinase 13-mediated process, which would account for the osteolysis associated with these tumors.[18]
Mutations in the H3F3A gene, present in over 90% of GCT, may drive tumorigenesis. These mutations are restricted to the stromal cell population and are not detected in the osteoclasts or their precursors.[19] The neoplastic stromal cell likely owns an immature osteoblast phenotype, part of whose transcriptional repertoire includes RANKL, besides other markers of the early osteoblast lineage.[20] It is also postulated that the stromal cells have become activated not because of some inherent genetic change but instead from a local hemorrhage-induced release of red cells and plasma proteins into the matrix. Unknown reciprocal giant cell signals may be involved in maintaining the stromal cells’ immature state. RANKL has been identified as a primary molecular target for therapy.[14]
On gross inspection, these lesions are characteristically chocolate brown, soft, spongy, and fragile.[21] Yellow-to-orange discoloration from the hemosiderin could also be present. Cystic blood-filled cavities within the tumor are common.[1] Examination reveals a variable degree of cortical expansion and disruption with an intact periosteum.[22]
Histologically, the lesions are cellular. Although the multinucleated giant cell is the characteristic cell type, these lesions have a background network of mononuclear stromal cells.[20] The mononuclear cells could be plump, oval, or spindle-shaped. They could have prominent mitotic activity, but cellular atypia is rare. Multinucleate giant cells have numerous centrally located nuclei in opposition to the peripherally located nuclei of Langerhans-type giant cells seen in atypical infections. The nuclei are compact and oval and contain prominent nucleoli. Giant cells are distributed throughout the lesion. The concentration of multinucleated giant cells differs from tumor to tumor. Some tumors have numerous multinucleated giant cells, whereas others have a small number of giant cells settled in whirls of spindle-shaped stromal cells. In approximately 5% of the cases, giant cells invade the small perforating vessels.
Three types of cells are found in benign bone GCT:[23]
Significant level activity for insulin-like growth factors I and II are found in type II and type III cells but absent in type I cells, which suggests that these factors are essential in the development and regulation of GCT.[1]
Genetically, 80% of individuals with GCT of the bone exhibit the cytogenetic abnormality of telomeric associations (tas), whereas half of the cells in the tumor show the tas abnormality.[27] The RANK pathway is often reported to be involved in the pathogenesis of GCT. This pathway is a crucial signaling pathway of bone remodeling that plays a critical role in the differentiation of precursors into multinucleated osteoclasts and activation of osteoclasts leading to bone resorption.[28]
The most common history and physical findings include:
The workup includes:
Surgical Resection
Adjuvant treatments (liquid nitrogen, phenol, or HO and argon beam coagulation) offers an excellent recurrence-free survival, especially when paired with an intralesional curettage. A successful treatment for GCT heavily relies on the aggressiveness of the intralesional curettage than on the specific adjuvant used. The adequacy of tumor removal is influenced by the tumor location, associated fractures, extensions to the soft tissue, and an understanding of the functional consequences of the resection.
Topical or systemic bisphosphonates like zoledronate or pamidronate can be used as a novel adjuvant therapy for GCT. Bisphosphonates induce apoptosis and limit the tumor progression by targeting the osteoclast-like giant cells.[50][51]
Denosumab, a monoclonal antibody, is widely used to treat unresectable GCTs of bone in adults and skeletally-matured adolescents, and acts by specifically binding to RANKL.
There is no recognized effective chemotherapeutic agent available for the management of these tumors yet.
Based on the radiographic findings, the differential diagnoses include:
As noted earlier, mutations within the H3F3A gene can distinguish GCT from other entities, as they are identified in up to 96% of cases.[53][54] However, a mutation in H3F3A does not entirely exclude malignancy in other osteoclast-rich tumors, like chondroblastoma, aneurysmal bone cyst, or non-ossifying fibroma.[45][47] Specifically, chondroblastomas have a high frequency of mutations in histone 3.3 genes.[55]
Different classifications of GCT have been described based on histology and clinical/radiographic appearance, although they are clinically less useful. Campanacci grading system is as follows:
Grade I – Intraosseous lesions with well-marginated borders as well as an intact cortex.
Grade II – More extensive intraosseous lesions associated with a thin cortex without loss of cortical continuity.
Grade III – Extraosseous lesions that extend into soft tissue.
A recurrence occurring after three years has been considered exceptional in the literature.[43] The local recurrence rate ranges from 20% to 50% averaging 33%.[36][56] Modern curettage techniques had led to an improvement in the GCT local control rate. Total serum acid phosphatase is suggested as a tumor marker to monitor the response to the GCT treatment. While an increase in tumor grade from I to III is not necessarily a reflection of the biologic aggressiveness of the tumor, there is an increase in the rate of recurrence in Grade III lesions. In very few cases, a true spontaneous transformation to malignancy has been reported.[57]
Pulmonary metastases account for about 16-25% of the reported cases. Pulmonary metastases are treated with wide resection, combined with interferon alfa, chemotherapy, and radiation. When these metastases cannot be fully excised surgically, adjuvant treatments, like radiation or chemotherapy, are generally recommended. For unresectable metastases, both chemotherapy and radiation therapy are implemented. Lung metastases can have poor outcomes.[58][59][60] Metastases of bone GCT are pretty rare, occurring in only about 3% of cases, but the behavior of pulmonary metastasis is unpredictable.[61][62][63] There is an increased risk in younger patients who develop a local recurrence with an Enneking stage-III disease, or present with axial involvement.[54] Metastatic lesions are similar to primary lesions histologically. The mean interval between the onset of the tumor and the detection of pulmonary metastasis is approximately 18 to 24 months.[54] Complete excision of the metastases has been very successful with good long-term survival, but those with comorbidity may eventually die from the metastases.[1]
There is a probability of the presence of a primary bone sarcoma within prominent areas of giant cell reaction and hemorrhage of a newly discovered GCT that was missed at the initial evaluation instead of a malignant transformation explanation.[64] Malignant transformations result in osteosarcoma, malignant histiocytoma, or fibrosarcoma. Malignant transformation can be found after 4-40 years from the initial surgery.[65]
Overall, GCT has a good prognosis. Pulmonary metastases cause death in 16-25% of the patients presenting them. When a true malignant transformation occurs within a GCT, the prognosis is much worse than for a benign GCT, but it is still somewhat better than for other high-grade sarcomas.
Giant cell tumor of the bone can be complicated with the following:
As the exact cause of GCT, like most of the other tumors, is still unclear, measures to deter them from occurring are unknown. It is crucial to educate the patients about the presentations of a local invasion or metastasis so that they can seek medical advice early in the process, which results in early detection and a better outcome. Education of the patient in regards to the surgical treatment is of utmost importance so they can make informed decisions that may impact the outcomes.
The patients with GCT benefit notably from an inter-professional team providing their care. Primary care providers or emergency physicians are typically the first to visit the patients. Chiropractors may also be the first to encounter a GCT on their radiographs and must refer the patient to the appropriate specialist. After obtaining a plain X-ray showing the bone tumor, the patient should be referred to an orthopedic surgeon. The radiologists provide interpretations of the images, and an orthopedic oncologist provides the appropriate surgical care. Nursing assists in all phases from the pre-op care to assisting in surgical and postoperative care.
Finally, the patient should receive rehabilitation from an occupational or physical therapist. Each of these disciplines is warranted to work together closely as a team to provide optimal care and achieve the best outcomes for the patients, which helps them get back to their ordinary daily activity as soon as possible.
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