Giant Cell Tumor

Author: Patrick O'Donnell

Topic updated on 05/16/13 11:08pm


Introduction
A benign aggressive tumor typically found in the epiphysis of long bones Age & sex more common in females (unlike most bone tumors which show male predominance) ages 30-50 years Location 50% occur around knee (distal femur or proximal tibia) 10% in sacrum and vertebrae (sacrum is most common site in axial skeleton) while GCT can rarely occur in the 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) spinal GCT typically occurs in the vertebral body 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
Bone scan
- is very hot
MRI
- shows clear demarcation on T1 image between fatty marrow and tumor

Histology

Characteristic findings
- neoplastic cell is the mononucleur stromal cell
- hallmark giant cells are numerous
  - nuclei of giant cell appears same as stromal cells
- secondary aneurysmal bone cyst degeneration is not uncommon

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
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

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

	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

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Qbank (9 Questions)

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(OBQ10.204) A 29-year-old female complains of increasing severity back pain for the past 4 months. Radiograph, CT scan, T1 and T2 MRI, and biopsy specimen are shown in Figures A through E. What is the most likely diagnosis? Topic

Review Topic

FIGURES: A

1. Osteosarcoma
2. Ewing's sarcoma
3. Lymphoma
4. Giant cell tumor
5. Chordoma

PREFERRED RESPONSE ▶

DISCUSSION: The history, radiographs, CT scan, MRI, and histology slide are consistent with a diagnosis of giant cell tumor of the sacrum. Outside the appendicular skeleton, the sacrum is a common location for giant cell tumor of bone. The radiographs and CT scan show a well defined lytic lesion. The characteristic MRI signal pattern of a lesion which isn't too bright nor too dark is seen on T2 and T1 MRI. This MRI signal is characteristic for giant cell tumor, lymphoma, and Ewing's sarcoma. The histology specimen shows multinucleated giant cells on a mononuclear stromal background. While the MRI appearance may be suggestive of either giant cell tumor, lymphoma, or Ewing's sarcoma, the histology specimen is classic for giant cell tumor. Histology slides for lymphoma and Ewing's sarcoma are shown in illustrations A and B. Note the classic Reed-Sternberg cells of lymphoma with granular cytoplasm and a eosinophilic nucleolus and the small round blue cells of Ewing's sarcoma.

Illustrations: A

REFERENCES:

1. Mirra JM. Bone Tumors. Philadelphia, PA: Lea and Febiger; 1989:941-1022.

2. McDonald DJ, Weber KL. Giant cell tumor of bone. In: Schwartz HS, ed. Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2007:133-140.

Question Authors:

Patrick O'Donnell MD/PhD, John Badylak MD, Jan Szatkowski MD,

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(OBQ09.50) Which of the following radiographs demonstrates a tumor that would be best treated by curettage with a power burr and packing with cement? Topic

Review Topic

FIGURES: A

1. Figure A
2. Figure B
3. Figure C
4. Figure D
5. Figure E

PREFERRED RESPONSE ▶

DISCUSSION: Figure E is representative of a Giant Cell tumor and appropriate treatment includes curettage with a power burr and packing with cement.

Bini et al conducted a Level 4 review of 38 patients treated with curettage through a cortical window and adjuvant packing of the defect with cement. They found a 95% good to excellent result with an 8% recurrence rate.

Turcotte discussed that giant cell tumors are primarily treated with extensive curettage and reconstruction with adjuvant treatment.

Incorrect Answers:
Answer 1: Figure A demonstrates an Adamantinonma (or osteofibrous dysplasia) which is typically treated with surgical wide excision.
Answer 2: Figure B is Fibrous Dysplasia which is typically treated with nonoperative management unless a fracture is present.
Answer 3: Figure C is an Osteochondroma which is typically treated with surgical resection.
Answer 4: Figure D is a Parosteal Osteosarcoma which is typically treated with wide surgical excision.

REFERENCES:

1. Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006. Jan;37(1):35-51. PMID:16311110 (Link to Abstract)

2. Bini SA, Gill K, Johnston JO. Giant cell tumor of bone. Curettage and cement reconstruction. Clin Orthop Relat Res. 1995 Dec;(321):245-50 PMID:7497676 (Link to Abstract)

Question Authors:

Michael Hughes MD, John Badylak MD,

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(OBQ08.252) A 33-year-old female reports lateral knee pain and slight fullness. She underwent a bone scan which showed increased activity isolated to the proximal fibula. Radiographs and histology are shown in Figures A and B. What is the most likely diagnosis? Topic

Review Topic

FIGURES: A

1. Parosteal osteosarcoma
2. Eosinophilic granuloma
3. Chondroblastoma
4. Giant cell tumor
5. Multiple myeloma

PREFERRED RESPONSE ▶

DISCUSSION: Giant cell tumor presents as a lytic lesion in the metaphysis and epiphysis of long bones, most frequently affecting the knee (as shown). It is characterized by proliferation of mononuclear stromal cells and the presence of multi-nucleated giant cells with homogenous distribution (figure B). Although benign, it is locally aggressive and deserves treatments that include extended curettage followed by cement or bone grafting. Malignancy is rarely associated with GCT but may be found in a recurrent tumor or years after irradiation of a previously benign GCT. The cited reference by Turcotte et al is a review article discussing the clinical presentation, evaluation, and treatment of giant cell tumors.

REFERENCES:

1. Turcotte et al. Giant cell tumor of bone. Orthopaedic Clinics of North America. 2006: 37: 35-51 PMID:16311110 (Link to Abstract)

Question Authors:

Greg Galano MD, Derek Moore, Eric Shirley MD,

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(OBQ07.186) Giant cell tumors of bone can be locally aggressive and result in significant bone destruction. Which of the following is responsible for this type of bone destruction? Topic

Review Topic

1. Multinuclear giant cells
2. Osteocytic stromal cells
3. Tumor cell activation of osteoclasts
4. Tumor cell inactivation of osteoblasts
5. Osteoprotegrin activation of osteoclasts

PREFERRED RESPONSE ▶

DISCUSSION: The bone destruction in giant cell tumors is caused by the tumor cell activation of the osteoclasts and the secondary osteoclast resorption of bone.

Benign and malignant tumor cells don't have the capacity to dissolve bone, only the osteoclast can accomplish this. While the RANK-RANKL interaction is likely related to the tumor induced osteolysis, osteoprotegrin (OPG) is an antagonist to this process. The multinuclear giant cells and the osteocytic stromal cells of giant cell tumor are locally aggressive, but they do not have the capacity to dissolve bone.

Illustration A show the complex interaction between the tumor cells, osteoclast precursors, and the activated osteoclast actively resorbing bone. While the exact mechanism of tumor-induced osteolysis is a topic of intense research, most authors agree it occurs due to a complex interaction between tumor induced RANKL activation of osteoclasts and the molecular action of matrix metalloproteinase with tumor growth factor-beta signaling at the tumor-bone interface.

Illustration B shows the effects of OPG which decreases tumor induced osteolysis by blockade of the RANK to RANKL interaction.

Illustration C shows a giant cell tumor of the proximal tibia in the epiphysis demonstrating tumor induced osteolysis caused by the neoplastic cell activation of local osteoclasts.

Illustrations: A

REFERENCES:

1. Vaccaro AR (ED). Orthopaedic Knowledge Update 8. American Academy of Orthopaedic Surgeons. Rosemont IL, AAOS 2004, pp 645-654

Question Authors:

Patrick O'Donnell MD/PhD, Ben Taylor MD, Patrick McCulloch MD, Ginger Holt,

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(OBQ07.197) A 40-year-old female presents with dull pain in her knee that has been increasing in severity over the past 6 months. Figures A through D show representative radiographs, mri, and biopsy section. What is the most appropriate treatment? Topic

Review Topic

FIGURES: A

1. Observation
2. Bone marrow biopsy
3. Intra-lesional curettage with local adjuvant therapy
4. Neoadjuvant chemotherapy, surgical excision, and adjuvant chemotherapy
5. Neoadjuvant radiotherapy and surgical excision

PREFERRED RESPONSE ▶

DISCUSSION: The history, radiographs, and histology are consistent with giant cell tumor, a benign aggressive tumor treated with intra-lesional curettage followed by local adjuvant therapy. While many authors advocate for one specific adjuvant therapy (argon beam, liquid nitrogen, cement with bisphosphonates) no adjuvant therapy has proven better than the rest. It appears rather that aggressive curettage with a high speed burr is likely the most important step in treatment. Figure D shows the classic histology for giant cell tumor where the nuclei of the stromal cells are identical to the nuclei of the giant cells.

REFERENCES:

1. Gitelis S, McDonald D, in Simon M, Springfield D (eds): Surgery for Bone and Soft Tissue Tumors. 1998, pp 181-205

Question Authors:

Patrick O'Donnell MD/PhD,

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(OBQ06.73) A 41-year-old male presents with 6 months of wrist pain and swelling. He is otherwise healthy and denies trauma. Clincal photograph, radiographs, MRI, and histology are shown in Figures A through E. What is the most likely diagnosis? Topic

Review Topic

FIGURES: A

1. Aneurysmal bone cyst
2. Giant cell tumor
3. Telangectatic osteosarcoma
4. High-grade osteosarcoma
5. Osteomyelitis

PREFERRED RESPONSE ▶

DISCUSSION: The photo, radiographs, MRI, and histology are consistent with giant cell tumor, a benign aggressive lesion common around the knee, pelvis, and distal radius. The histology photograph shows the bland osteocytic stroma with multi-nucleated giant cells, where all the nuclei of the stromal and giant cells are homogeneous, consistent with giant cell tumor. The extra-articular resected specimen is shown in Illustration A. While giant cell tumor is a "benign" lesion, a small percentage (~2-5%) can metastasize to the lungs. While telangectatic osteosarcoma should be considered based on the history of pain and the radiographic appearance, the histology slide is not characteristic. Telangectatic osteosarcoma histology would show dilated, blood-filled vascular spaces lined by malignant osteoblasts (Illustration B). Blackley et al evaluated whether curettage and reconstruction was equivalent to curettage with adjuvant treatment for giant cell tumors. They found no difference in recurrence suggesting that "the adequacy of the removal of the tumor rather than the use of adjuvant modalities is what determines the risk of recurrence." Kocher et al reviewed their results in 24 patients with giant cell tumors treated with reconstruction using osteoarticular allografts. They found an equivalent rate of tumor recurrence, little pain with common activities, and good function suggesting osteoarticular allografts can be used effectively for reconstruction in giant cell tumors.

Illustrations: A

REFERENCES:

1. Blackley HR, Wunder JS, Davis AM, White LM, Kandel R, Bell RS. Treatment of giant-cell tumors of long bones with curettage and bone-grafting. J Bone Joint Surg Am. 1999 Jun;81(6):811-20. PMID:10391546 (Link to Abstract)

2. Kocher MS, Gebhardt MC, Mankin HJ. Reconstruction of the distal aspect of the radius with use of an osteoarticular allograft after excision of a skeletal tumor. J Bone Joint Surg Am. 1998 Mar;80(3):407-19. PMID:9531209 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, Patrick McCulloch MD,

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(OBQ06.114) A 21-year-old man presents with a destructive lesion in his distal femur. A chest radiograph reveals multiple lung nodules. Which of the following tumors has the highest rate of lung metastases? Topic

Review Topic

1. Non-ossifying fibroma
2. Giant cell tumor
3. Aneurysmal bone cyst
4. Osteoid Osteoma
5. Hemangioma

PREFERRED RESPONSE ▶

DISCUSSION: Giant cell tumors of bone are benign lesions that can be locally aggressive. These tumors are typically treated with local resection and/or curettage. Radiation therapy is selectively used for tumors in difficult to resect locations (i.e. spine). Only about 1 to 9% of giant cell tumors show malignant behavior and metastasize, most commonly to the lungs. This stands in contrast to other skeletal tumors, which rarely metastasize to the lungs, making giant cell tumor, along with chondroblastoma, a unique entity in this regard. Risk factors for lung mets include local recurrence, the location of the primary giant cell tumor (distal radius, proximal femur, and sacrum), Musculoskeletal Tumor Society Stage 2 or 3 and an immunocompromised state. Treatment for giant tumor lung mets consists of surgical excision (lobectomy, wedge resection, etc...) with good survival rates (~80%) although nearly half of all patients require multiple resections.

REFERENCES:

1. Menendez LR (ed): Orthopaedic Knowledge Update: Musculoskeletal Tumors. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2002, pp 113-118.

2. Feigenberg SJ, Marcuz RB Jr, Zlotecki RA, et al: Whole lung radiotherapy for giant cell tumors of bone with pulmonary metastases. Clin Orthop 2002;401:202-208. PMID:12151897 (Link to Abstract)

Question Authors:

Guillem Lomas MD,

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(OBQ05.203) All of the following locations are common sites for giant cell tumor of bone to occur EXCEPT? Topic

Review Topic

1. Posterior elements of the spine
2. Distal femur
3. Sacrum
4. Distal radius
5. Proximal tibia

PREFERRED RESPONSE ▶

DISCUSSION: As reviewed by Robert Turcotte in the referenced article, the most common locations for giant cell tumor of bone to occur are about the distal femur/proximal tibia, distal radius, and the sacrum. The spine is an uncommon location for giant cell tumors, and when they occur, they usually occur in the vertebral body, not the posterior elements. In the axial skeleton, the sacrum is a common location for giant cell tumor of bone. Outside of the sacrum, giant cell tumor of bone is characteristically an epiphyseal/metaphyseal lesion. As discussed in the in vitro study by Gortzak et al, treatment of giant cell tumor of bone includes aggressive intralesional curettage augmented with adjuvant treatment like hydrogen peroxide, argon beam, liquid nitrogen, or phenol. Due to the morbidity of the surgical treatment, and the less than perfect long term outcome, adjuvant therapy with an antibody against RANKL called denosumab is currently being investigated in multiple centers across North America as described by Thomas et al in their phase 2 study. Denosumab inhibits osteoclast mediated osteolysis and treatment is associated with improved bone stock and sclerosis of the GCT lesions. While denosumab doesn't obviate the need for surgical excision, the resulting surgical procedure is less extensive and early data may suggest a decreased risk of local recurrence. While giant cell tumor of bone is a benign condition, there is a small chance for pulmonary seeding of giant cell metastases. This occurs in somewhere between 2-5% of patients with primary giant cells and occurs more often in patients with recurrent disease.

REFERENCES:

1. Unni, KK: Giant Cell Tumor Chapter ; Dahlin’s Bone Tumor, 1996

2. Gortzak Y, Kandel R, Deheshi B, Werier J, Turcotte RE, Ferguson PC, Wunder JS. The efficacy of chemical adjuvants on giant-cell tumour of bone. An in vitro study. J Bone Joint Surg Br. 2010 Oct;92(10):1475-9. PMID:21089702 (Link to Abstract)

3. Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006 PMID:16311110 (Link to Abstract)

4. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010 Mar;11(3):275-80. PMID:20149736 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, Patrick McCulloch MD, John Badylak MD,

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(OBQ05.240) Giant cell tumors of bone can occur in many different areas throughout the body. All of the following are common locations for giant cell tumors of bone EXCEPT? Topic

Review Topic

1. Sacrum
2. Distal radius
3. Tibial diaphysis
4. Distal femur
5. Phalanges of the hand

PREFERRED RESPONSE ▶

DISCUSSION: Giant cell tumors are one of the more common tumors in young adults 25-40 years of age. Giant cell tumors are common around the knee, distal radius, sacrum, and they are one of the most common tumors which arise in the phalanges of the hand. There is much argument as to whether giant cell tumors arise in the metaphysis or the epiphysis, but most authors agree that giant cell tumors are very uncommon in the diaphysis. Illustration A are radiographs classic for a giant cell tumor showing a large lytic metaphseal-epiphyseal lesion in the distal femur. Illustration B is an axial CT of the distal femur showing the lytic giant cell tumor, abutting and fracturing the subchondral bone. Illustration C is histology classic for a giant cell tumor where the nuclei of the multi-nucleated giant cells look identical to the nuclei of the stromal cells. Williams et al undertook a prospective study to evaulate the recurrence rate of giant cell tumors of the hand and they found that soft tissue extension of the tumor significantly increased the rate of local recurrence. This finding is significant because multiple previous studies have demonstrated similar higher recurrence rates for giant cell tumors with soft tissue extension in other areas like around the knee and the distal radius.

Illustrations: A

REFERENCES:

1. Williams J, Hodari A, Janevski P, Siddiqui A. Recurrence of giant cell tumors in the hand: a prospective study. J Hand Surg Am. 2010 Mar;35(3):451-6. PMID:20193861 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD,

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Cases

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Evidence & References Show References

Level of Evidence 3 (Retrospective Cohort Study or Case-Control Study)

Blackley HR, Wunder JS, Davis AM, White LM, Kandel R, Bell RS. Treatment of giant-cell tumors of long bones with curettage and bone-grafting. J Bone Joint Surg Am. 1999 Jun;81(6):811-20. PMID:10391546 (Link to Abstract)
Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010 Mar;11(3):275-80. PMID:20149736 (Link to Abstract)

Level of Evidence 4 (Case Series)

Bini SA, Gill K, Johnston JO. Giant cell tumor of bone. Curettage and cement reconstruction. Clin Orthop Relat Res. 1995 Dec;(321):245-50 PMID:7497676 (Link to Abstract)
Williams J, Hodari A, Janevski P, Siddiqui A. Recurrence of giant cell tumors in the hand: a prospective study. J Hand Surg Am. 2010 Mar;35(3):451-6. PMID:20193861 (Link to Abstract)

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Gortzak Y, Kandel R, Deheshi B, Werier J, Turcotte RE, Ferguson PC, Wunder JS. The efficacy of chemical adjuvants on giant-cell tumour of bone. An in vitro study. J Bone Joint Surg Br. 2010 Oct;92(10):1475-9. PMID:21089702 (Link to Abstract)
Turcotte et al. Giant cell tumor of bone. Orthopaedic Clinics of North America. 2006: 37: 35-51 PMID:16311110 (Link to Abstract)
Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006 PMID:16311110 (Link to Abstract)
Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006. Jan;37(1):35-51. PMID:16311110 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Gitelis S, McDonald D, in Simon M, Springfield D (eds): Surgery for Bone and Soft Tissue Tumors. 1998, pp 181-205
McDonald DJ, Weber KL. Giant cell tumor of bone. In: Schwartz HS, ed. Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2007:133-140.
Mirra JM. Bone Tumors. Philadelphia, PA: Lea and Febiger; 1989:941-1022.
Unni, KK: Giant Cell Tumor Chapter ; Dahlin’s Bone Tumor, 1996
Vaccaro AR (ED). Orthopaedic Knowledge Update 8. American Academy of Orthopaedic Surgeons. Rosemont IL, AAOS 2004, pp 645-654

Undefined

Feigenberg SJ, Marcuz RB Jr, Zlotecki RA, et al: Whole lung radiotherapy for giant cell tumors of bone with pulmonary metastases. Clin Orthop 2002;401:202-208. PMID:12151897 (Link to Abstract)
Kocher MS, Gebhardt MC, Mankin HJ. Reconstruction of the distal aspect of the radius with use of an osteoarticular allograft after excision of a skeletal tumor. J Bone Joint Surg Am. 1998 Mar;80(3):407-19. PMID:9531209 (Link to Abstract)
Menendez LR (ed): Orthopaedic Knowledge Update: Musculoskeletal Tumors. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2002, pp 113-118.

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Giant Cell Tumor

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