Summary Giant Cell Tumors are benign, aggressive tumors typically found in the epiphysis of long bones, most commonly at the distal femur and proximal tibia. Patients typically present between ages 30 and 50 with insidious onset of pain of the involved extremity with activity, at night, or at rest. Diagnosis is made with a biopsy showing mononuclear stromal cells that resemble interstitial fibroblasts with numerous giant cells dispersed throughout. Treatment is generally curettage, adjuvant treatment, and reconstruction as necessary depending on the location of the lesion. Epidemiology Incidence 1.7 per million people Demographics more common in females (unlike most bone tumors which show male predominance) ages 30-50 years Anatomic 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 spine it usually occurs in the vertebral body phalanges of the hand is also a very common location may arise in the apophysis (like chondroblastoma) Etiology Genetics mutations metastatic lesions often noted to have altertions in c-myc oncogene or p53 Associated conditions malignancy primary malignant giant cell tumor metastatic to lung in 2-4% of cases wrist and hand lesions have greater chance of metastasis secondary malignant giant cell tumor occurs following radiation or multiple resections of giant cell tumor Presentation Symptoms pain insidious onset of pain of the involved extremity with activity, at night, or at rest pain referable to involved joint night pain (result of tumor expansion) difficulty ambulating swelling Physical exam inspection & palpation palpable mass tenderness over mass soft tissue swelling if peri-articular lesion, joint effusion can be present motion decreased range of motion around affected joint gait antalgic Imaging Radiographs recommended views extremity involved chest x-ray to evaluate for lung metastasis findings 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 CT recommend views chest CT to evaluate for pulmonary metatases occurs in 1-6% findings lung metastases are usually benign (histologically similar to primary bone tumor) MRI indications to evalute for extent of lesion findings tumor blushing cystic degeneration shows clear demarcation on T1 image between fatty marrow and tumor dark on T1, bright on T2 and avid on gadolinium enhanced Bone scan findings Can be variable Studies Histology characteristic cells type I cell mononuclear 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 overexpression of RANKL by mononuclear stromal cells considered the instrumental pathogenic pathway denosumab functions to counteract this pathway Differential 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 Differential of Giant Cell tum Epiphyseal lesion Treatment is USUALLY curettage and bone grafting Giant Cell Tumor o o Chondroblastoma o o Aneurysmal Bone cyst o Osteoblastoma o Chondromyoid fibroma (CMF) o Treatment Nonoperative radiation therapy indications only indicated for inoperable or multiply recurrent lesions sacral lesions and large vertebral body lesions that are not ammendable to surgery outcomes leads to 15% malignant transformation medical management (denosumab, bisphosphanates) indications stabilize lesions augment or replace surgical management depending on the specific clinical scenario outcomes excellent response has been seen with denosumab (85-90% destruction of giant cells) post-surgical treatment with diphosphonate has shown to lower recurrence rates by 25-30% Operative extensive curettage, adjuvant treatment and reconstruction indications lesions amenable to currettage majority of lower extremity lesions hand lesion treatment is most controversial outcomes 20-40% recurrence with curettage and bone grafting alone versus 3-10% with addition of adjuvant treatment (phenol, hydrogen peroxide, cryo, argon beam, high-speed burr) complete resection and reconstruction indications when currettage not possible due to structural compromise with extensive involvement of vertebral body complete en bloc spondylectomy may be required outcomes the 10 year disease-free survival rates after total en bloc spondylectomy for GCT is reported to be 100% in some studies. amputation indications hand lesions with cortical breakthrough who are not amendable to intercalary resection outcomes has the lowest incidence of recurrence Techniques Radiation therapy technique external beam radiation Medical management technique bisphosphonates osteclast inhibitors which may decrease the size of the defect in giant cell tumors and help prevent post-surgical recurrence denosumab monoclonal antibody against RANK-ligand recent clinical trials suggest denosumab can decrease the size of the bone defect in giant cell tumor 85-90% tumor necrosis shows dramatic sclerosis and reconstitution of cortical bone after treatment complications bisphosphonates esophagitis, gastritis, long term use can lead to atypical subtrochanteric femur fractures denosumb may cause nasopharyngitis, arthralgias contraindications severe hypocalcemia Extensive curettage, adjuvant treatment and reconstruction extensive curettage 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 hand curettage is the most controversial if no cortical breakthrough treat with curettage and cementing if significant cortical breakthrough consider intercalary resection (with free fibular graft) vs. amputation adjuvant treatment technique phenol, liquid nitrogen, hydrogen peroxide, argon beam, high-speed burr can be effectively used in isolation or combination to reduce recurrence rates local recurrence rates with supplementation of ethanol and phenol are identical high-speed burr without any other adjuvant has a recurrence rate of 12% complications liquid nitrogen (aka cryotherapy) has been associated with an increased incidence of pathologic fracture and vascular injury reconstruction technique fill lesion with bone cement or bone graft and supplement with internal fixation structural allograft, endoprosthetic implants or combinations of two for large lesions or in setting of extensive bone destruction Complete resection and reconstruction approach based on location in the spine (lumbar, thoracic, cervical) anterior, posterior, or combined anterior approach in the lumbar spine may be direct lateral, oblique lateral or transperitoneal depending on specific level technique can be single or 2-staged procedure 1st stage would involve total vertebral spondylectomy, adjuvant treatment with the placement of a reconstruction expandable cage and anterior plating alternatively can use bone cement in lieu of a structural cage may require nerve root resection based on spinal level and involvement of nerve roots within tumor 2nd stage would involve bilateral laminectomy and excision of remaining soft tissues following by posterior instrumentation Amputation technique resection of phalangeal or metacarpal lesions with ray transfer or allograft reconstruction Complications Malignant transformation to high grade sarcoma incidence very rare (<1% prevalence) latency 9 years from previous radiation treatment 19 years from spontaneous transformation treatment surgical resection of metastatic lesions interferon treatment radiation Secondary ABC incidence between 10-14% differentiate from primary ABC because of enhancing soft-tissue component in GCT (not present in primary ABC) Recurrence incidence local recurrence occurs in 20% cases diagnose with CT guided biopsy risk factors not using adjuvant treatment during surgery Pathologic fracture risk factors peri-articular lesions using crytherapy as an adjuvant Prognosis Risk of malignancy < 5 % metastatic GCT has a 5 year 76% disease-free survival rate and a 17% mortality rate.