Giant cell tumor of bone

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rohan A. Bhimani, M.B.B.S., D.N.B., M.Ch.[2]

Synonyms and keywords: Osteoclastoma; Giant cell myeloma; Giant cell tumor; Giant cell tumor of the bone

Overview

Giant cell tumor of bone is a relatively uncommon tumor of the bone. It is characterized by the presence of multinucleated giant cells (osteoclast-like cells). Giant cell tumor of bone accounts for 4-5% of primary bone tumors and 18.2% of benign bone tumors. Giant cell tumor of bone almost invariably (97-99%) occur when the growth plate has closed and are therefore typically observed in early adulthood, with 80% of cases reported between the ages of 20 and 50, with a peak incidence between 20 and 30. Giant cell tumor of bone typically occur as single lesions. They usually prefers the epiphyses of long bones. Although any bone can be affected, the most common sites are distal femur, proximal tibia, and distal radius. The progression to giant cell tumor of bone usually involves the over-expression in RANK/RANKL signalling pathway with resultant over-proliferation of osteoclasts. On gross pathology, hemorrhage, presence of co-existent aneurysmal bone cyst, and fibrosis are characteristic findings of giant cell tumor of bone. On microscopic histopathological analysis, prominent and diffuse osteoclastic giant cells and mononuclear cells with frequent mitotic figures are characteristic findings of giant cell tumor of bone. Symptoms of giant cell tumor of bone include localized pain, localized swelling, and decreased range of motion. Physical examination findings will depend on the location of the giant cell tumor. Common physical examination findings of giant cell tumor are localized swelling and tenderness at the site of the tumor. Giant cell tumor of bone must be differentiated from aneurysmal bone cyst, chondroblastoma, simple bone cyst, osteoid osteoma, osteoblastoma, osteosarcoma, and brown tumor of hyperparathyroidism. X-ray may be helpful in the diagnosis of giant cell tumor of bone. Common complications of giant cell tumor include malignant transformation, recurrence, and metastasis. Findings on x-ray suggestive of giant cell tumor include metaepiphyseal location of mass and grow to the articular surface of the involved bone with narrow zone of transition. Surgery is the mainstay of treatment for giant cell tumor.

Historical Perspective

• In 1818, Cooper and Travers first described giant cell tumor (GCT) of bone.
• In 1845, Par H. Lebert described the first microscopic observations of multinucleated giant cells and fusiform cells as 'tumeur fiblastique'.
• In 1854, Sir James Paget provided the first description of the giant cell tumor in English literature.
• In early 1900, Bloodgood a surgeon at Johns Hopkins University, was credited with coining the term "giant-cell tumor" in his publication on radiographic features, conservative treatment, and use of bone grafts.
• In 1940, Jaffe and Lichtenstein described the clinical-radiographic-histologic identity of giant cell tumor.

Classification

• Giant cell tumor (GCT) can be classified based on imaging findings and on mechanism of origin.

Mechanism of Origin

Based on mechanism of origin, malignant giant cell tumor (MGCT) can be classified into:

Primary Malignant Giant Cell Tumor

• When MGCT arises de novo, it is called primary MGCT.
• Metastatizes to lung in 2-5%.

Secondary Malignant Giant Cell Tumor

• It occurs following radiation or multiple resections of giant cell tumor.

Enneking (MSTS) Staging System

• The Enneking surgical staging system (also known as the MSTS system) for benign musculoskeletal tumors based on radiographic characteristics of the tumor host margin.
• It is widely accepted and routinely used classification.

Stages	Description
1	Latent: Well demarcated borders
2	Active: Indistinct borders
3	Aggressive: Indistinct borders

Pathophysiology

• The exact pathogenesis of giant cell tumor (GCT) is not fully understood.
• Various theories have been proposed concerning the pathogenesis of giant cell tumor:
  • Over-expression in RANK/RANKL signalling pathway with resultant over-proliferation of osteoclasts.
  • The stromal cells are believed to be the major neoplastic and proliferative component of giant cell tumor.
  • The stromal cells often make osteoids, thus have the potential to differentiate into osteoblastic cells.
  • Monocytes derived from CD14- and CD34-positive precursor cells, which also express the chemokine receptor CXCR4.
  • Stromal cells in GCT secrete various chemokines including monocyte chemoattractant protein (MCP)-1 and SDF-1, which attract blood monocytes and stimulate their migration into tumor tissues.
  • The over-expression of interleukin 6 (IL6) in GCT has been seen as a further autocrin/paracrin factor connected with the formation of multinucleated giant cell.
• Giant cell tumor of bone typically occur in the epiphyses of long bones.
• The bones often involved by epiphyseal GCT are distal femur, proximal tibia, and distal radius.

Genetics

• Mutation in the histone 3.3 gene H3F3A (p.Gly34)is seen in approximately 92% of giant cell tumours of bone.
• A subset of the mutations can be easily detected using a G34W mutation specific antibody.

Causes

There are no established causes for giant cell tumor of the bone.

Differentiating Giant cell tumor of bone from other Diseases

Giant cell tumor of bone must be differentiated from:

• Brown tumor of hyperparathyroidism
  • It can look like GCT on radiographs except it occurs as multiple lesions and associated with serum calcium level abnormalities
• Chondroblastoma
  • It is epiphyseal in location
  • It may also demonstrate ABC formation
  • It has extensive surrounding soft tissue and marrow edema
  • Chondrblastoma have sclerotic margin and central calcification of chondroid matrix "ring and arcs" pattern
• Giant cell rich osteosarcoma
  • It occurs in metaphysis of the bone
  • It has bimodal age distribution; affecting adolescents and elderly.
• Chordoma
  • It mimics GCT in sacrum
  • It occurs in midline

Epidemiology and Demographics

• In the United States and Europe, giant cell tumors(GCT) represent approximately 5% of all primary bone tumors and 21% of all benign bone tumors.
• Giant cell tumors occur most commonly in the third decade of life; less than 5% of GCTs occur in patients who are skeletally immature.
• GCTs usually occur in patients older than 19 years.
• Women are more commonly affected than men, with a 1.5:1 ratio.
• There is no racial predilection to giant cell tumor.

Risk Factors

There are no established risk factors for giant cell tumor.

Screening

There is insufficient evidence to recommend routine screening for giant cell tumor.

Natural History, Complications, and Prognosis

• If left untreated, few patients with giant cell tumor may progress to develop lung metastasis.
• Common complications of giant cell tumor include:
  • Malignant transformation
    • Malignant transformation is far more common in men (M:F of ~3:1)
    • Sarcomatous transformation is observed, especially in radiotherapy treated inoperable tumors.
  • Secondary Aneurysmal bone cyst (ABC)
    • To differentiate from primary ABC based on enhancing soft-tissue component in GCT; which is not present in primary ABC.
  • Recurrence
    • Local recurrence rate of giant cell tumor of bone is about 10 to 40%.
    • Lucency is seen at bone-cement interface
    • It is diagnosed with CT guided biopsy
  • Pathologic fracture
  • Postoperative infection
    • There is an increased risk with en bloc resection followed by endoprosthesis.
• The prognosis of giant cell tumor is generally good, despite of recurrences and pulmonary metastases.
• The mortality rate due to giant cell tumour is about 4%.

Diagnosis

Diagnostic Study of Choice

• Biopsy is the diagnostic study of choice for the diagnosis of giant cell tumor.
• Gross pathological findings include:
  • Giant cell tumors are variable in appearance, depending on amount of hemorrhage, presence of co-existent aneurysmal bone cyst, and degree of presence fibrosis.
• Histopathological findings include:
  • Presence of numerous Cathepsin-K producing, CD33 +, CD14 - multinucleated osteoclast-like giant cells and plump spindle-shaped stromal cells that represent the main proliferating cell population.
  • The spindle-shaped mononuclear cells represents the neoplastic population and are characterized at the cytogenetic level by telomeric associations and a peculiar telomere-protecting capping mechanism.
• Areas of regressive change such as necrosis or fibrosis as well as extensive hemorrhage are frequently present.
• Frequent mitotic figures in the mononuclear cells may be seen, especially in pregnant women or those on the oral contraceptive pill, due to increased hormone levels.

History and Symptoms

Symptoms of giant cell tumor include:

• Localized bone pain
• Localized swelling
• Decreased range of motion of the affected joint
• Limp

Physical Examination

• Patients with giant cell tumor usually appears well.
• Common physical examination findings of giant cell tumor include:
  • Tenderness to palpation
  • Soft tissue swelling
  • Decreased range of motion
  • Muscle atrophy
  • Joint effusion
  • Involvement of adjacent structures such as peripheral nerves or veins

Laboratory Findings

There are no diagnostic laboratory findings associated with giant cell tumor.

Electrocardiogram

There are no ECG findings associated with giant cell tumor.

X Ray

• Three views of affected bone or joint are recommended.
• X-ray findings include:
• Eccentric metaphyseal location and grow to the articular surface of the involved bone
• Narrow zone of transition with a broader zone of transition is observed in more aggressive giant cell tumors
• No surrounding sclerosis
• Overlying cortex is thinned, expanded or deficient
• Periosteal reaction usually not seen
• No matrix calcification/mineralisation

Chest X-Ray

• Chest radiograph should be done to look for benign pulmonary metastasis which may occur with giant cell tumor.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with giant cell tumor.

CT scan

CT findings for giant cell tumor include:

• Absence of bone and intralesional mineralization

MRI

• MRI is performed to delineate the extent of the neoplasm.
• MRI findings of giant cell tumor of bone include:
  • T1: Low to intermediate solid component and Low signal periphery
  • T2: Intermediate to high signal
  • MRI may also reveal an effusion of the joint.

Bone Scan

• Increased uptake is observed around the lesion of giant cell tumor, especially around the periphery, with a central photopenic region (doughnut sign).
• Increased blood pool activity is also observed.

Other Diagnostic Studies

There are no other diagnostic studies associated with giant cell tumor.

Treatment

Medical Therapy

• Denosumab
  • It is recommended for the treatment of unresectable GCT of bone (GCTB) in adults and skeletally mature adolescents.
  • It is a monoclonal antibody against RANK-ligand.
  • It decreases the size of the bone defect in giant cell tumor.
  • It shows dramatic sclerosis and reconstitution of cortical bone after treatment.

• Bisphosphonates
  • They are osteclast inhibitors which may decrease the size of the defect in giant cell tumors.

Surgery

Surgery is the mainstay of treatment for giant cell tumor.

Extensive Curettage and Reconstruction with adjuvant treatment

Indications

• Lesions amenable to currettage
• Hand lesion treatment is controversial
• If no cortical breakthrough, then treat with curettage and cementing
• If significant cortical breakthrough, then intercalary resection with free fibular graft

Technique

• The challenge of treatment is to remove lesion while preserving joint and providing support to subchondral joint
• Extensive exterioration which is removal of a large cortical window over the lesion is required
• Lesion can be filled with bone cement or autograft/allograft bone.
• Synthetic grafts such as polymethylmethacrylate (PMMA) have improved patient recovery and tumor removal due to the graft's exothermic reaction that causes thermal necrosis of cells and innate inflammatory reaction.

Chemical Adjuvants Used

• Liquid nitrogen
• Alcohols
• Phenol
• Hydrogen peroxide
• Zinc chloride
• Argon Laser

Outcomes

• 10-30% recurrence with curettage alone verses 3% with adjuvant treatment (phenol, hydrogen peroxide, argon beam, etc)

Amputation

Indications

• Hand lesions with cortical breakthrough which are not amendable to intercalary resection.

Radiation Therapy

Indications

• Reserved for cases in which surgical treatment is not feasible.
• Tumors are in locations not amenable to operative treatment.
• Patients in whom a potential for significant morbidity from tumor relapse or subsequent surgery exists.

Technique

• Megavoltage radiation is used.
• Dose: 35 to 70 Gy

Primary Prevention

There are no established measures for the primary prevention of giant cell tumor.

Secondary Prevention

There are no established measures for the secondary prevention of giant cell tumor.

References

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