GIANT CELL TUMOR OF BONE
Benign-Aggressive Tumor | Epiphyseal Location | RANK-RANKL Pathway
Campanacci Grading System
Critical Must-Knows
- GCT is benign histologically but locally aggressive with high recurrence rates (10-50%)
- Eccentric epiphyseal location extending to subchondral bone is pathognomonic after physeal closure
- RANK-RANKL pathway drives osteoclastic giant cell recruitment - denosumab targets this
- Extended curettage with local adjuvants (phenol, PMMA, argon beam) is standard treatment
- Pulmonary metastases occur in 1-5% despite benign histology - requires chest CT surveillance
Examiner's Pearls
- "H3F3A mutations (G34W/L) present in over 90% of cases - pathognomonic molecular marker
- "Denosumab causes tumor ossification but may increase recurrence risk - controversial
- "Pathological fracture occurs in 10-20% and does NOT contraindicate curettage
- "Malignant transformation less than 1% - usually after radiotherapy (avoid radiation)
Clinical Imaging
Imaging Gallery
Critical Giant Cell Tumor Exam Points
RANK-RANKL Pathway
Neoplastic stromal cells produce RANKL which recruits osteoclast-like giant cells causing bone resorption. Denosumab (anti-RANKL antibody) blocks this pathway causing tumor ossification.
Denosumab Controversy
Preoperative denosumab ossifies tumor making curettage difficult. May increase recurrence risk due to incomplete removal of viable peripheral tumor. Reserved for unresectable cases or downsizing.
Local Adjuvants
Triple adjuvant technique: High-speed burr (removes 1-2mm margin), phenol cauterization (cytotoxic), and PMMA cement (thermal necrosis 70-80°C). Reduces recurrence from 50% to 10-20%.
Epiphyseal Location
Eccentric epiphyseal lesion extending to subchondral bone is diagnostic. Occurs after physeal closure (20-40 years). 85% around knee (distal femur 30%, proximal tibia 25%, distal radius 10%).
At a Glance Table
Quick Clinical Decision Guide
| Campanacci Grade | Radiographic Features | Treatment | Recurrence Risk |
|---|---|---|---|
| Grade I (Latent) | Intramedullary, intact cortex, thin sclerotic rim | Extended curettage + burr + phenol + PMMA | 10-15% with triple adjuvant |
| Grade II (Active) | Expanded bone, thinned cortex, no soft tissue | Extended curettage + burr + phenol + PMMA | 15-25% with triple adjuvant |
| Grade III (Aggressive) | Cortical destruction, soft tissue mass | Curettage vs resection, ± denosumab | 25-50% curettage alone, 10% resection |
| Grade III + Fracture | Cortical destruction with pathological fracture | Stabilize fracture, then curettage after healing | Similar to Grade III (20-30%) |
GIANTGiant Cell Tumor Key Features
Memory Hook:GIANT cells In epiphysis After closure Near knee with Tendency to recur!
BURPExtended Curettage Adjuvants
Memory Hook:BURP technique: Burr, Unroof, Reconstitute with cement, Phenol - reduces recurrence!
CAGECampanacci Grading Features
Memory Hook:CAGE grading: Cortex intact, Attenuated, Gone through, always Extends to subchondral!
Overview and Epidemiology
Giant cell tumor (GCT) of bone is a benign but locally aggressive neoplasm characterized by proliferation of mononuclear stromal cells (the neoplastic component) and abundant osteoclast-like multinucleated giant cells. Despite benign histology, GCT demonstrates aggressive local behavior with high recurrence rates (10-50%) and rare metastatic potential (1-5% pulmonary metastases).
Definition
GCT is defined as a primary bone tumor composed of three cell populations: (1) mononuclear histiocyte-like cells, (2) mononuclear spindle-shaped stromal cells (the neoplastic component with H3F3A mutations), and (3) multinucleated osteoclast-like giant cells containing 20-100 nuclei per cell. The tumor characteristically arises in the epiphysis of long bones after physeal closure.
Clinical Significance
Giant cell tumor is clinically important because: (1) it is locally aggressive with high recurrence rates requiring meticulous surgical technique; (2) eccentric epiphyseal location threatens joint function; (3) pathological fracture complicates 10-20% of cases; (4) RANK-RANKL pathway provides targeted therapy (denosumab) but with controversial outcomes; and (5) rare pulmonary metastases can occur despite benign histology.
Demographics
- Age: Peak 20-40 years (range 15-65 years)
- Gender: Slight female predominance 1.5:1
- Geographic: Higher incidence in Asian populations
- Timing: After physeal closure (skeletally mature)
Anatomical Distribution
- Distal femur: 30% (most common single site)
- Proximal tibia: 25%
- Distal radius: 10%
- Sacrum: 5-10%
- Around knee: 85% of all cases
Incidence
- Annual incidence: 1 per million population
- Comprises 5% of all primary bone tumors
- Represents 20% of benign bone tumors
- Accounts for 18% of all bone tumors biopsied
- Rare in children (under 2% before physeal closure)
Pathophysiology
Molecular Pathogenesis
H3F3A Mutation - Pathognomonic Marker
H3F3A mutations (encoding histone H3.3) are present in over 90% of GCT cases. The G34W or G34L amino acid substitutions are pathognomonic for GCT. These mutations drive RANKL overexpression by neoplastic stromal cells, which recruit osteoclast-like giant cells via the RANK-RANKL pathway.
RANK-RANKL Pathway in GCT Pathogenesis
- H3F3A G34W or G34L mutation in stromal cells
- Drives histone modification and gene dysregulation
- Results in RANKL overexpression
- Neoplastic stromal cells secrete RANKL (receptor activator of nuclear factor kappa-B ligand)
- RANKL is a key cytokine for osteoclast differentiation
- Creates local microenvironment favoring bone resorption
- RANKL binds RANK receptors on osteoclast precursors
- Stimulates fusion into multinucleated giant cells (20-100 nuclei)
- Giant cells are reactive (non-neoplastic) component
- Osteoclast-like giant cells resorb bone
- Tumor expands eccentrically in epiphysis
- Extends to subchondral bone (pathognomonic)
- Eventually breaks through cortex in Grade III
Denosumab Mechanism of Action
Denosumab is a fully human monoclonal antibody against RANKL. By blocking RANKL, denosumab prevents RANK activation on osteoclast precursors, inhibiting giant cell recruitment and bone resorption. This causes tumor ossification and size reduction. However, denosumab does NOT eliminate the neoplastic stromal cells, which may lead to recurrence when treatment stops.
Histological Features
Three Cell Populations
1. Multinucleated Giant Cells
- 20-100 nuclei per cell
- Osteoclast-like (reactive, not neoplastic)
- Express RANK receptor
- Evenly distributed throughout tumor
2. Mononuclear Stromal Cells
- Spindle-shaped (the neoplastic component)
- H3F3A mutations (G34W/L)
- Produce RANKL
- Ovoid nuclei similar to giant cell nuclei
3. Mononuclear Histiocyte-like Cells
- Round to ovoid cells
- Monocyte/macrophage lineage
- Osteoclast precursors
Microscopic Appearance
- Sheet-like growth pattern: No fibrous stroma
- Evenly distributed giant cells: Diagnostic feature
- Mitoses: Frequent in stromal cells (not giant cells)
- Hemorrhage: Common (causes ABC-like areas)
- Hemosiderin: Golden-brown pigment from hemorrhage
- Foam cells: Lipid-laden histiocytes in older lesions
Distinguishing GCT from Malignant Giant Cell Tumors
Key differences from osteosarcoma with giant cells:
- GCT has uniform nuclear features (stromal nuclei match giant cell nuclei)
- No osteoid or malignant bone production
- Sheet-like distribution without necrosis
- Mitoses in stromal cells are normal (not atypical)
Primary malignant GCT (less than 1%):
- Sarcomatous transformation within GCT
- Atypical stromal cells with malignant features
- Requires wide resection and chemotherapy
Biological Behavior
GCT Biological Characteristics
| Feature | Description | Clinical Implication |
|---|---|---|
| Local aggressiveness | Expands eccentrically, destroys cortex in Grade III | High recurrence risk (10-50%) requires meticulous surgery |
| Pulmonary metastases | 1-5% develop lung nodules despite benign histology | Baseline and surveillance chest CT required |
| Malignant transformation | Less than 1% (primary or radiation-induced) | Avoid radiotherapy except unresectable sacral lesions |
| Pathological fracture | 10-20% present with fracture | Does NOT contraindicate curettage after fracture healing |
Classification Systems
Campanacci Grading System
The Campanacci grading system classifies GCT based on radiographic appearance and guides surgical decision-making. Grade I and II are treated with extended curettage, while Grade III may require resection depending on reconstructability.
Campanacci Grading (Radiographic Classification)
| Grade | Radiographic Features | Cortical Integrity | Soft Tissue | Treatment |
|---|---|---|---|---|
| Grade I (Latent) | Well-defined intramedullary lesion with thin sclerotic rim | Intact cortex | None | Extended curettage + adjuvants |
| Grade II (Active) | Expanded lesion with thinned cortex, no sclerotic rim | Thinned but intact | None | Extended curettage + adjuvants |
| Grade III (Aggressive) | Ill-defined lesion breaking through cortex | Destroyed | Soft tissue mass | Curettage vs resection with or without denosumab |
Campanacci Grading in Practice
All three grades extend to subchondral bone (epiphyseal location is pathognomonic). The grading is based on cortical integrity, NOT distance from joint. Grade I has intact cortex, Grade II has thinned cortex, Grade III has cortical breakthrough. Recurrence rates increase with grade: I (10-15%), II (15-25%), III (25-50% if curettage alone).
Campanacci grading is the most widely used classification for GCT treatment planning.
Clinical Assessment
Clinical Presentation
The classic presentation is progressive pain localized to the involved bone, often for several months before diagnosis. Pain is typically activity-related initially, then becomes constant. Swelling may be present if the lesion is superficial. Pathological fracture occurs in 10-20% of cases.
Symptoms
- Pain: Progressive, localized bone pain (most common)
- Duration: Several months before diagnosis (median 6-12 months)
- Pattern: Initially activity-related, then constant
- Swelling: Visible if superficial (distal radius, proximal tibia)
- Fracture: Acute pain onset in 10-20% (pathological fracture)
Joint Symptoms
- Effusion: Knee effusion common (epiphyseal involvement)
- Stiffness: Loss of range of motion from pain
- Weakness: Antalgic gait or muscle inhibition
- Mechanical: Catching or locking if intra-articular extension
- Instability: Rare unless massive cortical destruction
Physical Examination
Systematic Examination Approach
- Swelling: Palpable mass if superficial (distal radius)
- Deformity: Bone expansion or angulation if fracture
- Skin: Normal overlying skin (not warm or red)
- Muscle wasting: Quadriceps atrophy if chronic knee pain
- Gait: Antalgic gait if lower extremity involved
- Tenderness: Localized bony tenderness over lesion
- Mass: Firm, non-mobile mass fixed to bone
- Temperature: Normal (not warm)
- Effusion: Knee effusion if distal femur or proximal tibia
- Neurovascular: Check distal pulses and sensation
- Active ROM: Limited by pain if juxta-articular
- Passive ROM: Similar limitation to active
- Strength: Reduced from pain inhibition or muscle atrophy
- Crepitus: May be present if pathological fracture
- Pathological fracture signs: Point tenderness, abnormal mobility
- Neurovascular: Comprehensive distal exam
- Lymph nodes: Assess for metastases (rare)
- Spine: Full neurological exam if sacral lesion
Red Flags for Malignant GCT or Metastases
Immediate evaluation needed if:
- Rapid symptom progression over weeks (suggests malignant transformation)
- Systemic symptoms (fever, weight loss, night sweats)
- Respiratory symptoms (suggests pulmonary metastases)
- Multiple bone lesions (GCT is almost always solitary)
- Age under 15 or over 65 (unusual for GCT, consider alternatives)
Investigations
Plain Radiography
Plain X-rays are the initial imaging modality and often highly characteristic. The classic appearance is an eccentric epiphyseal lytic lesion extending to the subchondral bone with no sclerotic rim or matrix mineralization.
X-ray Characteristics
- Location: Eccentric epiphyseal position (pathognomonic)
- Extension: Reaches subchondral bone (articular surface)
- Pattern: Geographic lytic lesion (well-defined)
- Matrix: No mineralization (purely lytic)
- Rim: No sclerotic margin (unlike ABC)
- Periosteal reaction: Absent unless fractured
Campanacci Grade on X-ray
- Grade I: Intramedullary, thin sclerotic rim, intact cortex
- Grade II: Expanded bone, thinned cortex, no rim
- Grade III: Cortical breakthrough, soft tissue mass
- Fracture: Cortical disruption with angulation or displacement
Radiographic Pearl
The soap bubble appearance on X-ray refers to multiple trabeculated compartments within the lytic lesion, creating a soap bubble pattern. This is less specific than the eccentric epiphyseal location extending to subchondral bone. No periosteal reaction unless pathological fracture present.
Computed Tomography (CT)
CT provides superior delineation of cortical integrity, trabecular destruction, and surgical planning. It is particularly useful for assessing Campanacci grade and planning cortical windows for curettage.
CT Protocol for GCT
- Thin slice CT (1mm or less)
- Bone and soft tissue windows
- Multiplanar reconstruction (coronal, sagittal)
- 3D reconstruction for surgical planning
- Cortical integrity and thickness (Campanacci grade)
- Trabecular architecture and destruction
- Soft tissue extension through cortex
- Proximity to neurovascular structures
- Planning cortical window location and size
- Baseline chest CT mandatory (rule out pulmonary metastases)
- 1-5% have lung nodules at presentation
- Nodules may be benign (implantation metastases)
- Serial imaging for surveillance
Magnetic Resonance Imaging (MRI)
MRI is essential for soft tissue evaluation, intra-articular extension, and surgical planning. It provides superior contrast resolution for identifying skip lesions and neurovascular involvement.
MRI Signal Characteristics of GCT
| Sequence | Signal Intensity | Clinical Significance |
|---|---|---|
| T1-weighted | Low to intermediate signal (hypointense to muscle) | Lesion extent in bone marrow, skip lesions |
| T2-weighted | Heterogeneous high signal (hyperintense) | Solid tumor with cystic/hemorrhagic areas (ABC-like) |
| T2 with fat saturation | Very high signal, fluid-fluid levels if hemorrhage | Distinguish solid vs cystic components |
| T1 + Gadolinium | Intense heterogeneous enhancement | Hypervascular tumor, distinguish from edema |
| STIR | High signal with extensive marrow edema | Marrow edema extent, intra-articular involvement |
MRI Fluid-Fluid Levels
Fluid-fluid levels on MRI are seen in 10-15% of GCT cases due to secondary aneurysmal bone cyst (ABC) formation from intra-tumoral hemorrhage. This does NOT indicate ABC as the primary diagnosis. The key is the solid enhancing tumor component (GCT) with superimposed cystic areas (secondary ABC). True ABC has thin rim enhancement only.
Biopsy
Histological confirmation is mandatory before definitive treatment. Biopsy should be performed by the treating surgeon or under their guidance to ensure excisable trajectory during curettage.
Biopsy Principles for GCT
Essential considerations:
- CT-guided core needle biopsy preferred (less contamination)
- Biopsy tract must be excisable during curettage (anterior approach for knee lesions)
- Multiple cores (3-5) from different areas (tumor heterogeneity)
- Avoid transarticular trajectory (risk of joint contamination)
- Send tissue for H3F3A mutation testing if diagnosis uncertain
- Expert musculoskeletal pathologist review mandatory
Biopsy Technique
- Approach: CT-guided core needle (11-14 gauge)
- Samples: Multiple cores (3-5) from different areas
- Trajectory: Plan for excision during curettage
- Avoid: Transarticular, transneural, or transgastrocnemius
- Frozen section: Can confirm GCT but not grade
Pathology Review
- Expert review: Musculoskeletal pathologist mandatory
- Differential: Rule out brown tumor, ABC, osteosarcoma with giant cells
- Molecular: H3F3A mutation (G34W/L) pathognomonic
- Grading: Not reliable (all GCT treated similarly)
- Malignant features: Atypical stromal cells, necrosis
Management Algorithm
The algorithm guides treatment from diagnosis through surveillance for optimal outcomes.
Surgical Technique
Extended Curettage with Triple Adjuvant Technique
Goal: Complete tumor removal with joint preservation and low recurrence risk (10-20%).
Extended Curettage Surgical Steps
- CT for cortical window planning (anterior or lateral based on lesion)
- MRI for soft tissue extent and neurovascular proximity
- Ensure biopsy tract can be excised during approach
- Plan for cement vs bone graft reconstruction
- Consent for recurrence risk (10-20% with adjuvants)
- Extensile approach to allow wide cortical window
- Excise biopsy tract en bloc with cortical window
- Create large cortical window (one-third to one-half circumference)
- Preserve intact cortical buttress for cement containment
- Identify tumor extent and soft tissue breakthrough
- Remove bulk tumor with large curettes (piecemeal)
- Extend curettage to all tumor margins under direct vision
- Remove soft tissue component if cortical breakthrough
- Identify and preserve articular cartilage
- Send representative tissue for final pathology
- Use high-speed burr to remove 1-2mm layer from entire cavity wall
- Creates mechanical margin beyond curettage plane
- Removes microscopic residual tumor in trabecular bone
- Irrigate copiously to remove bone debris
- Inspect cavity for complete trabecular removal
- Apply pure phenol to cavity wall with soaked gauze
- Leave in situ for 2-3 minutes (cytotoxic effect)
- Protect soft tissues and neurovascular structures with moist packs
- Irrigate with alcohol (neutralizes phenol), then copious saline
- Ensure complete phenol removal (prevent soft tissue necrosis)
- Mix PMMA bone cement (thermal necrosis reaches 70-80°C)
- Pack cement into cavity while liquid (maximizes thermal effect)
- Ensure cement reaches all recesses of cavity
- Allow polymerization (thermal adjuvant kills residual cells)
- Alternative: Bone graft if young patient and small defect
- Ensure hemostasis before closure
- Drain placement (remove at 24-48 hours)
- Layer-by-layer closure
- Immediate mobilization (cement provides instant stability)
- Protected weight-bearing if mechanical defect over 50% cortex
Triple Adjuvant Rationale
Each adjuvant targets a different mechanism:
- High-speed burr: Mechanical removal of 1-2mm margin (physically removes tumor cells in trabecular bone)
- Phenol: Chemical cytotoxicity (destroys residual cells on cavity surface)
- PMMA cement: Thermal necrosis 70-80°C during polymerization (kills cells beyond curettage margin)
Combination reduces recurrence from 50% (curettage alone) to 10-20% (triple adjuvant).
Surgical Pearls
- Wide cortical window allows visualization of entire tumor
- Preserve one cortical wall for cement containment
- Use angled curettes to reach all cavity recesses
- Burr removes trabecular bone but preserves cortical shell
- Phenol penetrates bone more than argon beam
- PMMA provides immediate stability (mobilize next day)
Pitfalls to Avoid
- Small cortical window (inadequate visualization)
- Incomplete curettage of soft tissue component
- Skipping adjuvants (increases recurrence risk)
- Phenol soft tissue contact (skin necrosis)
- Cement extravasation into joint (arthrofibrosis)
- Inadequate cement fill (residual tumor niches)
Complications
Treatment-Related Complications
Complications of GCT Treatment
| Complication | Incidence | Risk Factors | Management |
|---|---|---|---|
| Local recurrence | 10-20% (curettage + adjuvants), 5-10% (resection) | Incomplete curettage, no adjuvants, Grade III, soft tissue extension | Repeat curettage with adjuvants OR en bloc resection |
| Pathological fracture (postoperative) | 5-10% | Large defect (over 50% cortex), cement fracture, inadequate fixation | Protected weight-bearing, consider prophylactic fixation if high risk |
| Wound infection | 2-5% | Prolonged surgery, cement use, prior surgery | Antibiotics, debridement if deep, retain cement if well-fixed |
| Cement extravasation into joint | 1-5% | Subchondral lesion, inadequate cortical buttress | Arthroscopic removal if symptomatic, may cause arthrofibrosis |
| Phenol soft tissue necrosis | Under 1% | Inadequate protection of soft tissues during application | Prevention crucial, treat with debridement if occurs |
| Pulmonary metastases | 1-5% (benign lung nodules despite histology) | Grade III, recurrent disease, pathological fracture | Resection if few nodules, denosumab if multiple, surveillance |
| Malignant transformation | Under 1% | Prior radiation therapy, recurrent disease | Wide resection, chemotherapy as per sarcoma protocol |
Recurrence Management
Most recurrences (90%) occur within first 2 years. Early detection improves salvage outcomes.
Treatment of recurrence:
- First recurrence: Repeat extended curettage with adjuvants (success rate 70-80%)
- Second recurrence: Consider en bloc resection (curettage success rate drops to 50%)
- Multiple recurrences: En bloc resection or denosumab for palliation
Risk factors for recurrence:
- No adjuvant use (50% recurrence vs 10-20% with adjuvants)
- Grade III with soft tissue mass
- Incomplete curettage of soft tissue component
- Sacral or spinal location (difficult complete removal)
Postoperative Care
Immediate Postoperative Management
Postoperative Protocol
- Pain control (multimodal analgesia)
- Drain removal at 24-48 hours (output less than 50mL/24h)
- Mobilization on day 1 (cement provides instant stability)
- Ice and elevation for swelling
- DVT prophylaxis (mechanical and chemical)
- Wound check at 2 weeks
- X-ray at 2 weeks (assess cement position, rule out fracture)
- Protected weight-bearing if mechanical defect over 50% cortex
- Otherwise full weight-bearing as tolerated
- Gentle range of motion exercises (avoid stiffness)
- X-ray at 6 weeks and 3 months
- Progress to full weight-bearing (all cases)
- Strengthening exercises
- Return to activities of daily living
- Assess for early recurrence (pain, swelling)
- X-ray every 3 months for first year
- MRI at 6 months and 1 year (more sensitive for recurrence)
- Chest CT annually for 5 years (pulmonary metastases)
- Clinical exam every 3 months
- 90% of recurrences occur in first 2 years
Surveillance Protocol
Local Surveillance
Imaging schedule:
- X-ray every 3 months for year 1
- X-ray every 6 months for years 2-5
- MRI at 6 months, 1 year, 2 years (detects recurrence earlier than X-ray)
- CT if X-ray suspicious for recurrence
Clinical assessment:
- Pain or swelling (recurrence symptom)
- Range of motion and function
- Palpable mass if superficial
Pulmonary Surveillance
Chest imaging:
- Baseline chest CT at diagnosis
- Chest CT annually for 5 years
- Chest X-ray if CT not available (less sensitive)
Pulmonary metastases:
- Occur in 1-5% despite benign histology
- Usually asymptomatic (found on surveillance)
- Resect if few nodules (under 5)
- Denosumab if multiple or unresectable
When to Discharge from Surveillance
Discharge criteria after GCT treatment:
- 5 years disease-free (no local recurrence, no pulmonary metastases)
- 90% of recurrences occur in first 2 years, 98% by 5 years
- After 5 years, risk of late recurrence is less than 2%
- Discharge to primary care with instructions to return if new symptoms
Exceptions (continue surveillance beyond 5 years):
- Malignant GCT (lifelong surveillance as per sarcoma)
- Pulmonary metastases (annual chest CT lifelong)
- Denosumab-treated cases (higher recurrence risk, extend to 10 years)
Outcomes and Prognosis
Functional Outcomes
Favorable Prognostic Factors
- Campanacci Grade I-II: Lower recurrence risk
- Complete curettage with adjuvants: 10-20% recurrence vs 50% without
- No pathological fracture: Better bone stock for reconstruction
- Resectable location: Allows complete tumor removal
- Young patient: Better functional recovery and remodeling
Poor Prognostic Factors
- Campanacci Grade III: Higher recurrence (25-50% if curettage alone)
- Soft tissue extension: Difficult complete removal
- Sacral or spinal location: Inadequate surgical access
- Recurrent disease: Lower success rate with repeat curettage
- Pathological fracture: Tumor seeding into hematoma
Recurrence Rates by Treatment
Recurrence Rates by Surgical Technique
| Treatment Method | Recurrence Rate | Functional Outcome | Morbidity |
|---|---|---|---|
| Curettage alone (no adjuvants) | 40-60% | Excellent (joint preserved) | Low |
| Curettage + single adjuvant (burr OR phenol) | 25-35% | Excellent (joint preserved) | Low |
| Extended curettage + triple adjuvant (burr + phenol + PMMA) | 10-20% | Excellent (joint preserved) | Low to moderate |
| En bloc resection with wide margins | 5-10% | Good (joint sacrifice or prosthesis) | Moderate to high |
| Denosumab + curettage (neoadjuvant) | 20-50% (controversial - may be higher) | Variable (depends on tumor ossification) | Moderate |
Recurrence Pattern and Salvage
Recurrence characteristics:
- 90% of recurrences within first 2 years
- Usually at periphery of cement reconstruction
- Detected earlier on MRI than X-ray
- Salvage success rate: 70-80% after first recurrence, 50% after second
Salvage options:
- First recurrence: Repeat curettage with adjuvants (70-80% success)
- Second recurrence: En bloc resection (90% success) OR repeat curettage (50% success)
- Multiple recurrences: Denosumab for palliation if resection not feasible
Evidence Base
Triple Adjuvant Technique Reduces Recurrence in GCT
- 294 GCT cases treated with curettage, comparing adjuvant use
- Curettage alone: 59% recurrence rate
- Curettage + single adjuvant (burr OR phenol): 27% recurrence
- Curettage + triple adjuvant (burr + phenol + PMMA): 12% recurrence
- Statistical significance favoring triple adjuvant (p less than 0.001)
H3F3A Mutations Pathognomonic for Giant Cell Tumor
- Whole-genome sequencing of 15 GCT cases
- H3F3A mutations (G34W or G34L) identified in over 90% of GCT
- Mutations absent in other giant cell-rich tumors (chondroblastoma, ABC)
- Mutations drive RANKL overexpression in stromal cells
- Provides molecular diagnostic marker for uncertain cases
Denosumab for Unresectable Giant Cell Tumor: Efficacy and Controversy
- Phase 2 trial of denosumab 120mg monthly for unresectable GCT (n=282)
- Objective response rate 50% (tumor size reduction)
- Clinical benefit (response + stable disease) in 85%
- Median time to response 6 months
- Adverse events: hypocalcemia (13%), osteonecrosis of jaw (1%)
Pulmonary Metastases in Benign Giant Cell Tumor
- Systematic review of 2,984 GCT cases
- Pulmonary metastases incidence 1-5% despite benign histology
- Risk factors: Grade III, recurrent local disease, pathological fracture
- Lung lesions histologically benign but biologically metastatic
- Resection of solitary metastases curative in 50-70%
Campanacci Grading Predicts Recurrence and Treatment
- 327 GCT cases treated surgically with long-term follow-up
- Grade I recurrence 10% (curettage), Grade II 20%, Grade III 50%
- Resection reduced recurrence to 5-10% for all grades
- Grading based on cortical integrity predicts need for resection
- Pathological fracture did NOT increase recurrence if fracture healed first
Exam Viva Scenarios
Practice these scenarios to excel in your viva examination
Scenario 1: Classic GCT Presentation and Initial Management
"A 28-year-old female presents with 6 months of progressive left knee pain. X-ray shows a 4cm eccentric epiphyseal lytic lesion in the distal femur extending to the subchondral bone with thinned but intact cortex. MRI confirms a solid tumor with some cystic areas and marrow edema. How would you assess and manage this patient?"
Scenario 2: Grade III GCT with Soft Tissue Extension
"A 32-year-old male has a 6cm distal radius GCT with cortical destruction and a 3cm soft tissue mass. He is a professional violinist concerned about hand function. MRI shows extensive soft tissue extension but no neurovascular involvement. How would you approach this case?"
Scenario 3: GCT with Pathological Fracture
"A 25-year-old athlete presents to emergency with acute onset knee pain and inability to weight-bear after landing from a jump. X-ray shows a pathological fracture through a 5cm proximal tibial epiphyseal lytic lesion with 10 degrees of varus angulation. How would you manage this acutely and definitively?"
MCQ Practice Points
Epiphyseal Location Question
Q: What percentage of giant cell tumors occur around the knee, and what is the pathognomonic radiographic feature? A: 85% occur around the knee (distal femur 30%, proximal tibia 25%, distal radius 10%). Pathognomonic feature is eccentric epiphyseal location extending to subchondral bone after physeal closure (age 20-40 years). No sclerotic rim or matrix mineralization.
Molecular Marker Question
Q: What molecular mutation is pathognomonic for giant cell tumor of bone and how does it drive tumor pathogenesis? A: H3F3A mutations (G34W or G34L) are present in over 90% of GCT cases. These mutations in the histone H3.3 gene drive overexpression of RANKL by neoplastic stromal cells. RANKL recruits osteoclast-like giant cells via the RANK-RANKL pathway, causing bone resorption and tumor expansion.
Adjuvant Technique Question
Q: What is the triple adjuvant technique for GCT curettage and what is the mechanism of each adjuvant? A: Triple adjuvant technique:
- High-speed burr: Mechanical removal of 1-2mm margin from cavity wall (removes microscopic tumor in trabecular bone)
- Phenol cauterization: Chemical cytotoxicity to cavity surface for 2-3 minutes (destroys residual cells)
- PMMA cement: Thermal necrosis reaching 70-80°C during polymerization (kills cells beyond curettage margin)
Reduces recurrence from 50% (curettage alone) to 10-20% (triple adjuvant).
Denosumab Question
Q: What is the mechanism of action of denosumab in GCT and what is the controversy regarding its use? A: Denosumab is a monoclonal antibody against RANKL. It blocks RANK-RANKL pathway, preventing osteoclast recruitment and causing tumor ossification and size reduction.
Controversy:
- Proponents: Downsizes Grade III allowing joint-sparing surgery
- Critics: Ossifies tumor making complete curettage difficult, viable tumor persists at periphery, studies show higher recurrence (20-50% vs 10-20%)
- Current consensus: Reserve for truly unresectable cases (sacrum, spine), not routine Grade I-II
Campanacci Grading Question
Q: Describe the Campanacci grading system for GCT and how it guides treatment decisions. A: Campanacci grading based on cortical integrity:
- Grade I: Intramedullary with intact cortex and thin sclerotic rim → Extended curettage + adjuvants (10-15% recurrence)
- Grade II: Expanded bone with thinned but intact cortex, no rim → Extended curettage + adjuvants (15-25% recurrence)
- Grade III: Cortical destruction with soft tissue mass → Curettage vs resection, consider denosumab (25-50% recurrence if curettage alone)
All grades extend to subchondral bone. Grading determines surgical approach and predicts recurrence risk.
Pulmonary Metastases Question
Q: What is the incidence of pulmonary metastases in GCT and how are they managed? A: Pulmonary metastases occur in 1-5% of GCT cases despite benign histology. Lung nodules are histologically benign but biologically metastatic (implantation metastases). Baseline and annual chest CT mandatory for 5 years.
Management:
- Few nodules (under 5): Surgical resection (curative in 50-70%)
- Multiple nodules: Denosumab therapy or observation (many remain stable)
- Progressive disease: Denosumab 120mg monthly
Presence of lung nodules does NOT indicate malignant transformation.
Australian Context
Giant cell tumor of bone occurs at an annual incidence of approximately 1-1.5 per million population in Australia, representing 25-35 new cases per year. The condition is managed at specialized tertiary bone tumor units including Peter MacCallum Cancer Centre (Melbourne), Royal North Shore Hospital (Sydney), Princess Alexandra Hospital (Brisbane), Royal Adelaide Hospital, and Sir Charles Gairdner Hospital (Perth). All suspected GCT cases require urgent referral to these centers for multidisciplinary tumor board discussion and specialized management.
Denosumab (Xgeva 120mg) for giant cell tumor is PBS-listed under Authority Required (Streamlined) for unresectable tumors, recurrent disease after surgery where further surgery is not feasible, and metastatic disease. The PBS criteria require histological confirmation and management by a specialist with bone tumor experience. Patients require loading doses on days 1, 8, 15, and 29, followed by 120mg subcutaneous injections every 4 weeks with ongoing calcium and vitamin D monitoring to prevent hypocalcemia.
The Australian referral pathway requires GPs to refer suspected bone tumors urgently (within 2 weeks) to orthopaedic surgeons for initial assessment. Local surgeons should not perform biopsies but should arrange comprehensive imaging (X-ray, CT, MRI, chest CT) and refer to tertiary centers for CT-guided biopsy and definitive treatment. Extended curettage with adjuvants and en bloc resection procedures are performed exclusively at tertiary centers with bone tumor expertise, ensuring optimal outcomes and appropriate long-term surveillance protocols.
GIANT CELL TUMOR OF BONE
High-Yield Exam Summary
Key Features
- •Benign but locally aggressive, 5% of primary bone tumors, 20% of benign
- •Peak age 20-40 years (after physeal closure), slight female predominance 1.5:1
- •Eccentric epiphyseal location extending to subchondral bone (pathognomonic)
- •85% occur around knee (distal femur 30%, proximal tibia 25%, distal radius 10%)
- •Recurrence rate 10-20% with triple adjuvant, 50% without adjuvants
Pathophysiology and Histology
- •H3F3A mutations (G34W/L) in over 90% - pathognomonic molecular marker
- •RANK-RANKL pathway: stromal cells produce RANKL recruiting giant cells
- •Three cell populations: giant cells (20-100 nuclei), stromal cells (neoplastic), histiocytes
- •Sheet-like growth, evenly distributed giant cells, no fibrous stroma
- •Pulmonary metastases 1-5% despite benign histology (implantation metastases)
Campanacci Grading
- •Grade I: Intramedullary, intact cortex, thin sclerotic rim (10-15% recurrence)
- •Grade II: Expanded bone, thinned cortex, no rim (15-25% recurrence)
- •Grade III: Cortical destruction, soft tissue mass (25-50% recurrence curettage alone)
- •All grades extend to subchondral bone (articular surface involvement)
- •Grading determines treatment: I-II curettage, III curettage vs resection
Imaging
- •X-ray: Eccentric epiphyseal lytic lesion, no sclerotic rim, no mineralization, soap bubble
- •CT: Assess cortical integrity (Campanacci grade), trabecular destruction, surgical planning
- •MRI: Low T1, high T2, intense enhancement, fluid-fluid levels if ABC component (10-15%)
- •Chest CT: Mandatory baseline and annual surveillance (1-5% pulmonary metastases)
- •Biopsy: CT-guided core needle, excisable trajectory, H3F3A mutation testing
Treatment Algorithm
- •Grade I-II: Extended curettage + triple adjuvant (burr + phenol + PMMA cement)
- •Grade III resectable: Extended curettage + adjuvants OR en bloc resection
- •Grade III unresectable: Neoadjuvant denosumab 3-6 months then curettage
- •Pathological fracture: Immobilize 6-12 weeks for healing, then curettage
- •Recurrence: Repeat curettage (70-80% success) OR en bloc resection (90% success)
Triple Adjuvant Technique
- •High-speed burr: Removes 1-2mm margin from cavity wall (mechanical adjuvant)
- •Phenol cauterization: Apply 2-3 minutes, neutralize with alcohol (chemical adjuvant)
- •PMMA cement: Thermal necrosis 70-80°C during polymerization (thermal adjuvant)
- •Reduces recurrence from 50% (curettage alone) to 10-20% (triple adjuvant)
- •Wide cortical window essential for complete visualization and curettage
Denosumab Therapy
- •Anti-RANKL monoclonal antibody, blocks osteoclast recruitment
- •Indication: Unresectable Grade III (sacrum, spine), metastatic, recurrent
- •Dosing: 120mg subcutaneous days 1,8,15,29 then monthly, minimum 3-6 months
- •Controversy: Ossifies tumor (difficult curettage), may increase recurrence (20-50%)
- •Discontinue 4-6 weeks before surgery (rebound growth risk if continued)
Surveillance Protocol
- •X-ray every 3 months year 1, every 6 months years 2-5
- •MRI at 6 months, 1 year, 2 years (more sensitive for recurrence than X-ray)
- •Chest CT annually for 5 years (pulmonary metastases surveillance)
- •90% of recurrences within first 2 years, 98% by 5 years
- •Discharge at 5 years if disease-free (except malignant or metastatic cases)