Giant Cell Tumor - Pathology

Introduction

A benign aggressive tumor typically found in the metaphysis of long bones
Age & sex
- more common in females (unlike most bone tumors which show male predominance)
- ages 30-50 years
Location
- distal femur > proximal tibia > distal radius > sacral ala
- 50% occur around knee (distal femur or proximal tibia)
- 10% in sacrum and vertebrae (sacral ala is most common site in axial skeleton)
  - in the mobile spine, it usually occurs in the vertebral body
- distal radius is third most common location
- phalanges of the hand is also a very common location
- may arise in the apophysis (like chondroblastoma)
Malignancy
- primary malignant giant cell tumor
  - metastatic to lung in 2-5%
  - hand lesions have greater chance of metastasis
- secondary malignant giant cell tumor
  - occurs following radiation or multiple resections of giant cell tumor

Symptoms

Symptoms
- pain referable to involved joint
Physical exam
- palpable mass
- decreased range of motion around affected joint

Imaging

Radiographs
- eccentric lytic epiphyseal/metaphyseal lesion that often extends into the distal epiphysis and borders subchondral bone
- "neo-cortex" is characteristic of benign aggressive lesions, and not unique to GCT
Chest radiograph or chest CT
- pulmonary metatases occurs in 1-6%
- lung metastases are usually benign (histologically similar to primary bone tumor)
Bone scan
- is very hot
MRI
- shows clear demarcation on T1 image between fatty marrow and tumor

Histology

Characteristic cells
- Type I cell
  - mononucleur stromal cell that resembles interstitial fibroblasts
  - this is the neoplastic/tumor cell
  - has features of mesenchymal stem cells
- Type II cell
  - from monocyte/macrophage family recruited from peripheral blood
  - precursors of giant cells
- Type III cell
  - numerous giant cells are the hallmark of this lesion
  - nuclei
    - nuclei of giant cell appears same as stromal cells
    - multiple nuclei (up to 50 per cell)
  - similar characteristics as osteoclasts and resorb bone
    - have same enzymes (tartrate resistant acid phosphatase, carbonic anhydrase II, cathepsin K, vacuolar ATPase)
- secondary ABC degeneration is not uncommon
Molecular biology
- Type II and III cells have IGF-I and IGF-II activity
- 80% of patients with GCT have telomeric associations (tas) abnormality in half the cells
- RANK pathway is important
  - denosumab acts on this pathway

Treatment

Nonoperative
- radiation alone
  - indications
    - only indicated for inoperable or multiply recurrent lesions
  - outcomes
    - leads to 15% malignant transformation
- medical management
  - indications
    - medical therapy can be used to augment or replace surgical management depending on the specific clinical scenario
  - medications
    - bisphosphonates
      - osteclast inhibitors which may decrease the size of the defect in giant cell tumors
    - denosumab
      - monoclonal antibody against RANK-ligand
      - recent clinical trials suggest denosumab can decrease the size of the bone defect in giant cell tumor
        
        90% tumor necrosis
      - shows dramatic sclerosis and reconstitution of cortical bone after treatment
Operative
- extensive curettage and reconstruction (with adjuvant treatment)
  - indications
    - lesions amenable to currettage
    - hand lesion treatment is controversial
      - if no cortical breakthrough treat with curettage and cementing
      - if significant cortical breakthrough consider intercalary resection (with free fibular graft) vs. amputation
  - technique
    - challenge of treatment is to remove lesion while preserving joint and providing support to subchondral joint
    - extensive exterioration (removal of a large cortical window over the lesion) is required
    - can fill lesion with bone cement or autograft/allograft bone
  - 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 who are not amendable to intercalary resection

Complications

Malignant transformation (<1% prevalence)
- to high grade sarcoma (poor prognosis)
- latency
  - 9 years for previous radiation treatment
  - 19 years for spontaneous transformation
Secondary ABC (≤14%)
- differentiate from primary ABC because of enhancing soft-tissue component in GCT (not present in primary ABC)
Recurrence (15-25%)
- lucency at bone-cement interface
  - diagnose with CT guided biopsy
Pathologic fracture
- poorer outcome
Postoperative infection
- increased risk with en bloc resection + endoprosthesis

Differentials & Groups

Brown tumor of hyperparathyroidism
- can look like GCT on radiographs except it occurs as multiple lesions and associated with serum calcium level abnormalities
Chondroblastoma
- epiphyseal location
- may also demonstrate ABC formation
- has extensive surrounding soft tissue and marrow edema
- may have sclerotic margin and central calcification of chondroid matrix "ring and arcs" pattern
Osteosarcoma
- telangiectatic OS
- giant cell-rich OS
- fibroblastic OS
Chordoma (mimics GCT sacrum)
- occurs in midline

	Epiphyseal lesion	Treatment is USUALLY currettage and bone grafting⁽¹⁾
Giant Cell Tumor	•	•
Chondroblastoma	•	•
Aneurysmal Bone cyst		•
Osteoblastoma		•
Chondromyoid fibroma (CMF)		•

ASSUMPTIONS: (1) assuming no impending fracture

IBank

	Location	Xray	Xray	CT	B. Scan	MRI	MRI	Histo⁽¹⁾
Case A	knee -recurrence
Case B	knee
Case C	distal radius
Case D	hand
Case B	knee
Case B	ankle
Case A	humerus

(1) - histology does not always correspond to clinical case