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.

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.
  • 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.
• 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:

• Aneurysmal bone cyst
• Chondroblastoma
• Simple bone cyst
• Osteoid osteoma
• Osteoblastoma
• Osteosarcoma
• Giant cell reparative granuloma
• Brown tumor of hyperparathyroidism
• Non-ossifying fibroma

Gross Pathology

• Macroscopically, giant cell tumors are variable in appearance, depending on amount of hemorrhage, presence of co-existent aneurysmal bone cyst, and degree of presence fibrosis.

Microscopic Pathology

• Giant cell tumor of bone is characterized by the 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 are believed to represent 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 observed, especially in pregnant women or those on the oral contraceptive pill (due to increased hormone levels).

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.

Natural History, Complications and Prognosis

Complications

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.

• Recurrence

• Local recurrence rate of giant cell tumor of bone is 10 to 40%.
• Recurrence rates are higher when the tumor bone arises at a surgical inaccessible location locations such as spine and sacrum.

• Metastasis

• Giant cell tumor of bone may occasionally metastasize to vital organs such as the lung. Hence, this entity has been called benign metastasising giant cell tumor.

Prognosis

• The prognosis of giant cell tumor is generally excellent.

Diagnosis

History and Symptoms

• Patients usually present with pain and limited range of motion caused by tumor's proximity to the joint space.
• There may be swelling as well, if the tumor has been growing for a long time.
• Some patients may be asymptomatic until they develop a pathologic fracture at the site of the tumor.

Physical Examination

Physical examination findings will depend on the location of the giant cell tumor. Most giant cell tumors are located in the long bone of extremities.

Extremities

A palpable firm non tender or tender mass may be appreciated on physical examination. The assessment of giant cell tumor during physical examination include:

• Size
• Location
• Involvement of adjacent structures (such as peripheral nerves or veins)
• Edema

X Ray

X-ray may be helpful in the diagnosis of giant cell tumor of bone. Findings on x-ray suggestive of giant cell tumor include:

• Metaphyseal location and grow to the articular surface of the involved bone
• Narrow zone of transition: a broader zone of transition is observed in more aggressive giant cell tumors
• No surrounding sclerosis: 80-85%
• Overlying cortex is thinned, expanded or deficient
• Periosteal reaction is only observed in 10-30% of cases
• Soft tissue mass is not infrequent
• Pathological fracture may be present
• No matrix calcification/mineralisation

(Images courtesy of RadsWiki)

• 

  Giant cell tumor: Distal part of the femur

• 

  Giant cell tumor: Distal part of the femur

MRI

Typical signal characteristics on MRI of giant cell tumor of bone include:

T1:

• Low to intermediate solid component
• Low signal periphery
• Solid components enhance, helping distinguish giant cell tumor with aneurysmal bone cyst from pure aneurysmal bone cyst
• Some enhancement may also be observed in adjacent bone marrow

T2:

• Heterogenous high signal with areas of low signal intensity (variable) due to haemosiderin or fibrosis
• If an aneurysmal bone cyst component present, then fluid-fluid levels can be observed
• High signal in adjacent bone marrow thought to represent inflammatory edema

T1 C+ (Gd):

• Solid components will enhance, helping differentiate from aneurysmal bone cyst

Scintigraphy: Bone Scan

• Most giant cell tumors demonstrate increased uptake on delayed images, especially around the periphery, with a central photopenic region (doughnut sign).
• Increased blood pool activity is also observed, and can be observed in adjacent bones due to generalised regional hyperaemia.

Treatment

The treatment of giant cell tumor is directed towards local control without sacrificing joint function. Surgery is the mainstay of treatment for giant cell tumor.

Surgery

• Classically, treatment is with curettage and packing with bone chips or polymethylmethacrylate (PMMA).
• Local recurrence is from the periphery of the lesion and has historically occurred in up to 40-60% of cases.
• Newer intraoperative adjuncts such as thermal or chemical treatment of the resection margins have lowered the recurrence rate to 2.5-10%.
• Wide local excision is associated with a lower recurrence rate, but has greater morbidity.

References

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