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Basics of Giant Cell Tumor of bone (GCTB)
- 1. Giant cell tumor of bone aka Osteoclastoma Dr Bishwa Bandhu Niraula
- 2. Epidemology • 15% of benign bone tumor, F>M • Age: 30-50 years, Site: Metaepiphyseal region • Genetics: A/w alteration in c-myc oncogene, p53 • Incidence: 1.7 per million population • Site: Around knee> Sacrum> Distal radius> Proximal humerus> Vertebrae Campbell’s Operative Orthopedics: Textbook
- 3. Associated condition • Primary Malignant GCT • Metastasis to lung in 2-4% • Wrist and Hand lesions • Secondary Malignant GCT • occurs following radiation • multiple resections of giant cell tumor Incidence of Malignant GCT < 5%
- 4. WHO 2013 • A/t WHO 2013, 3 tumors compromise osteoclastic giant cell-rich tumor group • Giant cell lesion of small bone • Giant cell tumor of bone (GCTB) • Malignancy in GCTB Textbook: Therese J Blockage et al. Bone and Soft tissue tumor a multidisciplinary approach
- 5. What are giant cells • Monocyte/Macrophage lineage cells • Recruited from peripheral bloodstream • Not of osteoclastic lineage (type III) • Numerous centrally located nuclei (vs Langerhans GC- peripherally located) • Distributed throughout the lesion • Not the malignant component, rather a recruited reactive one Textbook: Therese J Blockage et al. Bone and Soft tissue tumor a multidisciplinary approach
- 6. Introduction: • Tumor containing multinucleated Giants cells • Chondroblastoma • NOF • Benign fibrous histiocytoma • Osteosarcoma • Giant cell reparative granuloma • Aneurysmal bone cyst • Browns tumor of hyperparathyoidism Textbook: Therese J Blockage et al. Bone and Soft tissue tumor a multidisciplinary approach
- 7. Types of cell in giant cells/ Histology Type 1 cells: • Neoplastic • Mononuclear Stromal Cells • Features of MSC’s Type 2 cells: • Monocyte/macrophage • Recruited from peripheral bloods • The GIANT CELLS Type 3 Cells: • Giant cells like cells • Numerous • Similar characteristics as osteoclast • Resorbs bone
- 8. How to differentiate Giant cell like lesion from GCT Nuclei of mononuclear stromal cells are identical to nuclei of Giant cells
- 9. Proposed theory for Primary GCT • Reactive response to vascular insufficiency in epiphysis • Profound hypoxia and hemorrhage • Activation of osteoblast like cells, recruits monocyte and osteoclasts • Pro-osteoclastic environment formation • Osteoblast and monocyte contribution • Associated genetic abberations, telomeric association • Why skeletally mature bones? • Why females? • Why distal knee,radius, sacrum • Why females? • Why aggressive and whys lungmets? Thus affects vascularly delicate areas like epiphysis Textbook: Therese J Blockage et al. Bone and Soft tissue tumor a multidisciplinary approach
- 10. Clinical features: Pain Swelling Joint Effusion Antalgic gait Pathological fractures Campbell’s Operative Orthopedics: Textbook
- 11. Pulmonary metastases • Usually in patients in distal radius or hand • Fate: Spontaneous regression or asymptomatic • 3% incidence, Overall mortality from Lung mets ~15% • Despite mortality Histology remained Benign • Recurrent lesions or aggressive lesions (stage 3) at higher risk • Follow up with CXR and extremity xray; • 3-4m/2 years, 6m at following year, f/b annual followup Campbell’s Operative Orthopedics: Textbook
- 13. Grading on radiology? Guess the grade??
- 14. MRI
- 15. MRI • T1= Intraosseous lesion, marrow extension • T2= soft tissue extension of tumor IN GCT • T1= dark • T2= bright Contrast: • areas of hypervascularity and enhancement with a very heterogeneous signal pattern
- 16. 55mm x 44.3 mm
- 18. CT scan • To aid in findings detectable in X-ray and MRI • Evaluation of cortical integrity • Not usually done
- 19. Other modality • Bone Scan: Least useful, may be wrongly interpreted
- 20. Metastatic workup • Thorax evaluation to see metastases, 2% • Cannon ball lesion may be seen • HRCT/CECT thorax
- 21. Evaluation of local recurrence • Progressive lysis of bone graft • Following curettage and cementation, • Osteolysis by thermal injury measures 2 mm surrounds cement • Radiolucent zone is bordered by thin outer sclerotic rim for about six months • Progressive lysis or failed sclerotic rim between cement and cancellous bone = recurrence
- 22. Evaluation of local recurrence • Usually recurrence occurs in Parent bone, BUT • Soft tissue implantation can occur during surgery • Soft tissue recurrence visible on plain radiographs • WHY? • Soft tissue has tendency towards peripheral calcification Recurrence rate with Curettage? Recurrence rate with extended curettage? 30-50% 15%
- 23. Differential Diagnosis • ABC (metaphyseal, young age), can be coexisting • Chondroblastoma (Epiphyseal, young) • Brown tumor of hyperPTH (always do Serum PTH in multifocal GCT) • Chondromyxoid fibroma • Telangiectatic Osteosarcoma • Osteoblastoma • LCH
- 24. Tumor Age and gender Site C/F Imaging Histology Treatment Remarks GCT 20-40; F>M Knee, Radius, Sacrum Pain, Path Fracture(10- 30%) Eccentric, radiolucent, No reactive bone, Cortical destruction, no matrix calcification Type 1,2,3 cells Extended curettage, resection, irradiation for irresectable, Resection of lung mtes Risk of lung mets < 5% ABC Young; M=F Knee, Humerus, Spine Pain, Swelling, Path fracture Expansile, eccentric, lytic lesion, no matrix mineralisation, fluid fluid level Cavernous space, blood filled endothelial lining Sclerosant, curretage and bone grafting rarely done Associated lesion, telangiectatic OS Chondroblasto ma 10-25 yrs, M:F= 2:1 Knee, Prox Humerus Mimic chronic synovitis Well circumscribed, epi or apophysis, cross open physis, matrix calcification(+) Chicken wire calcifiaction, Multinucleat ed giant cells, A/w 2o ABC Extended curettage, Resection of lung mets 1% incidence of lung mets
- 25. Tumor Age, gender Site C/F Imaging Histology Treatment Remarks Chondromy xoidfibrom a 10-30 y, M>F Proximal tibia Pain, asymptomatic Well circumscribed, Rim of reactive bone Lobules of Hypocellular myxoid cartilagenous tissue, lobule separed by fibrous tissue Extended Curettage Rule out Chondrosar coma Osteoblast oma 10-30, M:f= 3:1 Posterior Spinal elements Pain, painful scoliosis, Neurologic symptoms Sclerotic lesion in posterior elements Fibrovascular stroma, osteoid, osteoblastic rim Extended Curettage or resection, Stabilisation in spine Rule out low grade osteosarco ma LCH <20y, M:f= 2:1 Vertebral body, flat bones Painful, Asymptomatic , mimic OM Vertebrae plana, permeative, aggressive, Very benign to aggressive, Multifocal, Skull Large histiocytic cells, abundant nuclei, S-100 positive, Birbeck granules in electron Microscopy Observation, Steoids, Curettage, Chemo for systemic disease A/w HSC disease and Letterer Siwe disease ( more fatal)
- 27. 1 year follow up
- 29. Medical Management • Radiation Therapy: EBRT • leads to malignant transformation in 15% • Reserved for surgically inoperable tumor • Least Practised Fig: Image Guided RT setup in AIIMS Rishikesh
- 30. Adjuvant therapy Bisphosphonates Denosumab Interferon If planned for curettage If planned for excision
- 31. Bone environment and Mechanism Bone formation: • Promoted by stimulated osteoblasts Bone resorption: • Promoted by stimulated osteoclasts • RANKL and PTHrP Factors stimulating osteoblasts: • OPG • Calcitonin • Estrogen • TGF-beta • IL-10 Factors stimulating osteoclasts: • RANK-L • PTH • IL-1 • 1-25 OH2 vitamin D • PG-E2 • IL-6 (MM)
- 32. Mode of action of Bisphosphonates • Prevent formation of Osteoclast ruffled borders microtubules, causing apoptosis • Inhibition of osteoclasts, interferes with normal bone healing and remodeling • Nitrogen containing: (Alendronate(O), Risedronate(O), Pamidronate(IV), Zolendronate(IV)) • Inhibits osteoclast farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol pathway) • Non-nitrogen containing: (Clodronate, Etidronate) • Induce osteoclasts to undergo premature death and apoptosis • Does so by forming a toxic adenosine triphosphate (ATP) analogue
- 33. Zolendronic Acid • Nitrogen containing bisphosphonates • Most commonly Used in clinical practice • 4mg IV slowly over 30-45 mins • Every weekly for 3-5 doses • Used if planned for CURETTAGE
- 34. Zolendronic Acid • Complications: • Jaw Osteonecrosis • Atypical Subtrochanteric and femoral Stress Fracture
- 35. • 4 patients with Sacral GCT + Cauda Equina • Intralesional curettage + zoledronic acid-loaded bone cement for adjuvant local control • Mean tumor volume of 472.8 cm3 • No local recurrence observed x follow-up of 28 months • All patients had new bone regeneration on radiograph • All patients suffering from cauda equina syndrome were recovered 28m post-op
- 36. 28m post-op
- 37. Denosumab • Humanized monoclonal AB to RANK-L • inhibits osteoclastic activity • Inhibits RANK-RANKL interaction • Inhibits Giant cells and GC mediated osteolysis • Results in reduction in osteoclast-induced bone destruction • Dosage: 120 Mg SC • 0-7-14-28-(every months x n)
- 39. Interferon therapy • Initially used for viral infection, acted by inhibiting protein synthesis • Act on the cells that exhibit basic fibroblast growth factor (BFGF) • Cells of GCT overexpress BFGF, will respond to interferon therapy • Inhibits angiogenesis • Limitation: • Increased administration frequency, prolonged use • Allergic manifestation, flaring of autoimmune disorders
- 40. Interferon therapy • 45 doses of interferons alfa-2b • Dose of 3 miu/m2 SC on alternate days x 3 months • Full course of therapy of 45 cycles over 90 days on an alternate day Assessment: • Clinical • Radiological • CT and MRI (Choi density/size criteria (ICDS) and Response Evaluation Criteria in Solid Tumor (RECIST) ) • Histopathology
- 41. Upcoming roles of Newer agent • Simvastatin • Tyrosine kinase inhibitors: Apatinib and Sunitinib • Cabozantinib, another tyrosine kinase inhibitor • Norcantharidin, an anticancer drug No Strong evidence Xu R, Choong PFM. Metastatic giant cell tumour of bone: a narrative review of management options and approaches. ANZ J Surg. 2022 Apr
- 42. Upcoming roles of Newer agent No Strong evidence Xu R, Choong PFM. Metastatic giant cell tumour of bone: a narrative review of management options and approaches. ANZ J Surg. 2022 Apr
- 43. Basics before surgery Textbook: Turek
- 44. Surgery • Intralesional curettage: • Extended Curettage: • Mechanical • Chemical • Thermal • Argon Laser Textbook: Turek
- 45. Adequate cortical bone after intralesional curettage to maintain or restore bone stability Yes No Excision and Recon. Intact Cortex > 2/3rd or >5mm subchondral bone Yes Not necessary to fill the cavity, protected WB No >5mm subchondral bone after curettage No Yes Recon subchondral area(5-8mm thick) with morcellized autograft/allograft Residual Cavity Fill with Bone graft +/- PPMA Textbook: Turek
- 46. Mechanical • High Speed Burr- 50,000++ RPM • Aided by dental Mirror • Size of cavity =? • Size of lesion for adequate curettage
- 47. Chemical • Phenol • Hydrogen Peroxide • PMMA • 3 cycles each lasting minimum of 5 minutes • Protect Surrounding tissue
- 48. Benefit of Using Bone cement • Monomer of Bone Cement is Cytotoxic • Thermal effect • Immediate Structural Support, Rapid weightbearing ambulation • Contours well to the cavity geometry • Easy to detect tumor recurrence • A/w lower recurrence Campbell’s Operative Orthopedics: Textbook
- 49. Why autograft is not preferred? • Limited Stock, SSI • Implantation of tumor into harvest site • Non weight-bearing for prolonged period • Tumor recurrence difficult to distinguish from graft resorption Campbell’s Operative Orthopedics: Textbook
- 50. Liquid Nitrogen • Rapid freezing induces intracellular ice crystallization • propagation of ice mediates mechanical stress, which causes damage to cellular organelles. • Ice recrystallization accompanied by slow thawing mediates further damaging stress • To achieve a promising lethal effect tumor cells, • minimum intracellular freezing of −50° C to −70° C • Freezing rate greater than −20° C/minute advised • Thawing < 10°C /min required • The ultimate goal is to eradicate tumor cells without damage to the adjacent healthy tissues. Wu PK, Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone. Clin Orthop Relat Res. 2017 Jun
- 51. Freezing Nitrogen Ethanol Composite • Directly pouring liquid nitrogen into bone cavity first introduced by Marcove • Complications of liquid nitrogen treatment : • Caused directly by spills or overflow of the liquid • Liquid nitrogen’s freezing effect (−196° C) damaging adjacent normal tissues • Freezing nitrogen ethanol composite: • Exhibits similar cooling effects in a semisolid phase • No need to pour freezing liquid into surgical field Wu PK, Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone. Clin Orthop Relat Res. 2017 Jun
- 52. Freezing Nitrogen Ethanol Composite • Freshly prepared freezing nitrogen ethanol composite froze to −136° C • achieved −122° C isotherm across a piece of 10 ± 0.50-mm-thick bone • Freezing rate of −34° C per minute, temp expected to tumor-killing requirements Wu PK, Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone. Clin Orthop Relat Res. 2017 Jun
- 53. Wide local excision • Reconstruction with Megaprosthesis • Revision- MUTARS(Modular Universal Tumor and Revision System) • Amputation (Reserved)
- 54. Take Home Message • GCT, benign but aggressive, epimetaphyseal lesion, lung mets <5% • Radiologically diagnosed, confirm with Biopsy, Always do CT thorax • Surgical management with adjunct therapy helpful • Denosumab for excision, Zoledronate for Curettage • Higher Recurrence • Extended curettage helpful
- 55. Thank You