Giant cell tumors of bone

A rare usually benign tumor.

Affects primarily 20-40 year olds.

Can destroy bone and can cause pain, impair range of motion and cause bone fractures.

Locally aggressive.

A relatively uncommon tumor of the bone.

Characterized by the presence of multinucleated giant cells.

Contains osteoclast-like giant cells and stromal cells.

Giant cells are found at the perimeter of areas of bone erosion.

The spindle-like stromal cells are the neoplastic component of GCTB, owing to their ability to proliferate readily.

H3F3A mutations are frequent in GCTB.

Giant cells  express receptor activator of nuclear factor Kappa B and are stromal cells express RANKL ligand.

RANKL drives osteoclast formation, function, and survival, and excessive RANKL expression causes an increase in bone lysis and destruction.

Malignancy is uncommon and occurs in approximately 2% of all cases.

Malignant degeneration tends to metastasize to the lungs.

Usually benign with unpredictable behavior.

Histologically appear benign, even at distant sites.

Causes synovium, bursae, and tendon sheaths to overgrow and damaging surrounding tissue.

The tumor can occur in large or small joints.

Most commonly found in long bones-distal femur, proximal tibia, but can occur at any bony site.

Estimated incidence is 1.7 cases per million persons and pink incidence occurs in the third and fourth decades of life with slight female predominance.

Composed of three different cell populations.

The giant-cell tumour stromal cells constitute the neoplastic cells, which are from an osteoblastic origin and are classified based on expression of osteoblast cell markers such as alkaline phosphatase and ostocalsin.

The mononuclear histiocytic cells and multinucleated giant cell fractions are secondarily recruited and comprise the non-neoplastic cell population derived from an osteoclast-monocyte lineage determined primarily by expression of CD68, a marker for monocytic precursor cells.

Lesions contain 2 distinct populations of cells: tumor cells and osteoclast like population of monocytic origin.

Signaling through receptor activator of nuclear factor kappa B ligand (RANKL), a member of the tumor necrosis factor ligand family, is strongly expressed.

Usually the tumors develop slowly, but may recur locally in as many as 50% of cases.

Accounts for 4-5% of primary bone tumors and about 20% of benign bone tumors.

Higher incidence rates are observed in Asia, where it constitutes about 20% of all primary bone tumors.

Slightly more common in females.

Has a predilection for the epiphyseal/metaphyseal region of long bones,

Generally occurs in the third to fourth decades of life.

Observed to metastasize to the lungs in up to 5% of cases.

In 1-3% of cases can transform to the malignant sarcoma phenotype.

Patients usually present with pain and limited range of motion caused by the lesion’s proximity to the joint space.

Some patients remain asymptomatic until they develop a pathologic fracture at the site of the tumor.

The symptoms may include muscular aches and pains.

May also experience nerve pain.

Have a epiphyseal location and grow to the articular surface of the involved bone.

May show characteristic ‘soap bubble’ appearance on x-ray, and usually have a non-sclerotic and sharply defined border.

5% of giant-cell tumors metastasize, usually to lung.

A chest x-ray or CT may be needed to rule out metastases.

MRI can assess intramedullary and soft tissue extension.

Diagnosis based on biopsy findings with multinucleated giant cells.

Surgery is the treatment of choice for resectable lesions.

Intralesional curettage is commonly added in include high speed burring, alcohol/phenol, and argon beams.

Intralesional surgery, with or without local adjuvant, or en block resection is the treatment of choice for giant  cell tumor of bone.

Recurrence rates remain high,10-50%, and surgery for common locations such as the pelvis and spine have unacceptably high morbidity.

For patients with tumors in the axial skeleton, recurrent disease, and locally advanced disease: surgical management not be recommended and could have significant adverse effects on mobility.

Curettage is a commonly used.

Tumors can often occur.

Arterial embolization for locally unresectable disease is the initial treatment of choice.

Patients with tumors that are not amenable to surgery are treated with radiation therapy.

Unfortunately the majority of recurrent tumors with transformations to the malignant sarcoma phenotype have been in patients that have received radiotherapy for their primary benign lesion.

Treatment includes bisphosphonates thought to induce apoptosis in the multinucleated giant cell fraction, preventing tumor-induced osteolysis.

Humanized monoclonal antibodies such as Denosumab targeting the RANK ligand (RANKL) have been employed in treatment.

Denosumab Is approved for treating giant cell tumors of the bone.

Denosumab is useful for lesions that are unresectable or when resection will cause severe morbidity.

Denosumab indicated for use in patients who are not candidates for resection of the tumors or when surgery is likely result in severe morbidity.

Denosumab should be used only in adolescents whose bones have matured.

Denosumab has an 86% response rate of eliminating of 90% of giant cells and no X-ray progression up to 25 weeks (Thomas D et al).

Denosumab shows long-term disease control for patients with GCTB: 88% of patients with an resectable disease had no progression or recurrence of disease after 60 months of follow up.

Interferon results in prolonged remissions.

The first drug approved for the treatment of adults with symptomatic tenosynovial giant cell tumor is Pexidartinib (Tutlio).

Pexidartinib Inhibits the expression of colony stimulating factor 1 that occurs with giant cell tumor.

Pexidartinib most common adverse events are hair color changes, fatigue, increased liver function tests, and nausea,

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