Giant cell tumour (GCT) is still one of the most obscure and
intensively examined tumours of bone. Its histogenesis is
uncertain. The histology does not predict the clinical outcome; and there are still many unanswered questions with
regard to both its treatment and prognosis.
The World Health Organisation has classified GCT as
an aggressive, potentially malignant lesion,1 which means
that its evolution based on its histological features is unpredictable. Statistically, 80% of GCTs have a benign course,
with a local rate of recurrence of 20% to 50%. About 10%
undergo malignant transformation at recurrence and 1% to
4% give pulmonary metastases even in cases of benign histology.
Pathogenesis
GCT is a true neoplastic process originating from the undifferentiated mesenchymal cells of the bone marrow. Multinucleated giant cells and mononuclear stromal cells can be
distinguished by light microscopy. These giant cells are
derived from stromal cells, either by the fusion of mononuclear cells or, less probably, by amitotic division or
nuclear segmentation of the stromal cells without the corresponding cytoplasmic division.2 These multinucleated giant
cells resemble osteoclasts in their phenotype and function:
their size is approximately 60 m; their numerous nucleoli
are centrally located in the cytoplasm. They stain positive
for tartrate-resistant acid phosphatase and naphthyl alpha
esterase enzymes,3 and possess receptor sites for calcitonin,
a phenotypic marker for osteoclasts.
Further histochemical, immunohistochemical, cytogenetic, and molecular-genetic studies in cell cultures
derived from GCTs have confirmed that there are two differ-
Clinical appearance
M. SZENDRI
Rate of local
recurrence
(%)
Goldenberg et al17
(multicentre)
Campanacci et al12
Capanna et al52
(multicentre)
Lausten et al85
Richardson and
Dickinson62
Blackley et al51
McDonald et al35
Capanna et al52
(multicentre)
Szendri29
Komiya and Inoue63
Gitelis et al46
120
None
43
128
490
None
None
30
45
None/radiotherapy
(Burr) none
56
0
12
34
17
ODonell et al49
Bini et al57
Malawar and Dunham59
Labs et al48
60
38
102
15
Burr, none
Burr, phenol, alcohol
PMMA,* phenol,
liquid nitrogen
Phenol, PMMA
Burr, PMMA
Burr, phenol, alcohol,
PMMA
PMMA/burr phenol
PMMA
(Burr)+liquid nitrogen
PMMA
Author/s
18
16
59
85
187
11
11
16
9
0
0
25
8
7.9
12
* polymethylmethacrylate
Fig. 1
Photograph showing the gross pathology of a GCT. The defect in the proximal tibia is filled by extensive soft fleshy tissue and the cortex is destroyed
(surface of transsected specimen).
Fig. 2a
Fig. 2b
Radiographs showing a) a grade-2 active GCT of the tibia and b) within one year progression of the tumour from the
tibia to the head of the fibula.
Frankly sarcomatous stroma is juxtaposed to areas of typical GCT.15 Secondary malignant GCT (5% to 10% of all
GCTs)36 may develop during recurrence of a benign GCT,
or undergo a malignant transformation after radiotherapy.
On very rare occasions, the development of a bone sarcoma
has been seen after a very long period (18 to 25 years) after
the treatment of a primary GCT.37
Benign metastasing GCTs have been described in 1% to
3% of all and 6% of the recurrent GCTs.38-40 In these cases
the histology of the nodules found in the lung is identical to
that of the benign tumour of the primary site. Some authors
explain this as secondary to the tumour emboli often seen in
the peripheral vessels of GCTs and regard the nodules found
in the lung as implants and not as true metastases.41,42
Others30,43 have not found any correlation between the frequency of finding tumour emboli in vessels and that of pulmonary involvement. Recent basic studies have shown
enhanced matrix metalloproteinases, expression of p53 protein and overexpression of the C-myc oncogene in metastasising GCTs.7,44 Lung metastases usually appear two to
three years after the treatment of the primary tumour.38,45
They have also been occasionally observed at the first presentation of a benign GCT. A chest radiograph is therefore
justified both at the first presentation and in the course of the
follow-up.
Treatment
In most benign aggressive bone tumours control can be
achieved by wide surgical excision. Following en-bloc
M. SZENDRI
Fig. 3a
Fig. 3b
GCT in the distal part of the radius. Figure 3a Radiograph showing the lytic lesion with an ill-defined border to normal bone. Figure 3b MRI showing a high
signal on the T2-weighted image, representing
necrotic areas in the tumour tissue. Figure 3c Radiograph showing en-bloc resection of the tumour and
transposition of the fibular autograft. There have been
no symptoms for four years.
Fig. 3c
lesion, taking into account the higher probability of recurrence. It is also important to know whether it is the first,
second or third recurrence. Although repeated recurrences
have little influence on the final outcome in most cases and
can be treated by curettage as for the primary lesion, it is
customary to deal more radically35 with recurrences.
The treatment of choice in most GCTs is curettage and
bone grafting. Historically,12,17 however, curettage has been
associated with a high rate of recurrence (30% to 50%,
Table I) and therefore different adjuvants have been introduced. These presumably remove the tumour cells which
remain after curettage because of their thermal (liquid nitrogen, methylmethacrylate) or chemical (phenol, hydrogenperoxide, alcohol) effects.29,49,51-56
The use of cement has advantages in that it is cheap, and
immediate weight-bearing is allowed. Furthermore, a local
recurrence is easily recognised around the cement both by
radiographic and MR investigations.28,49,57 Extended curettage and application of bone cement are therefore the most
accepted methods in the treatment of GCT.
Rinsing the curetted defect with liquid nitrogen seems to
be the most effective treatment for local control of the
tumour. Malawer et al58 observed a rate of recurrence of
only 7.9% after cryosurgery in 102 patients with GCT.
However, because the depth of the necrotic margin is difficult to control, there is a high risk of bone and skin necrosis
and fracture.59-61
Good results have been published recently of the use of
high-pressure pulsatile lavage and a high-speed dental burr,
which allows the surgeon to remove the contaminated
margin up to normal bone.16,51,62
The data summarised in Table I suggest that the use of
adjuvants combined with careful curettage may decrease the
rates of local recurrence, which were reported in the historical series of Goldenberg et al17 and Campanacci et al12 as
being from 30% to 43% and 8% to 17%. Some authors
found no recurrence either with63 or without46,62 the use of
additional adjuvants, but the number of the patients reported
was small. It is of interest that Blackley et al51 using a highspeed burr at the time of curettage and bone grafting
achieved a very acceptable rate of recurrence with 12% in
59 patients.
Complete removal of the tumour tissue is more difficult
when the tumour is in the distal part of the radius or in the
metacarpal bones. There are reports that GCT in the radius
is more aggressive and metastasises more often to the
lung.38-40,51,64-66 En-bloc resection is strongly recommended especially in grade-3 tumours. When the distal part
of the radius is removed, an ulnocarpal arthrodesis can be
performed,67 or the defect can be replaced by either nonvascularised (Fig. 3) or vascularised autologous fibula.47,61
Treatment is especially difficult when the GCT has
affected the vertebral column,68 the sacrum or the periacetabular region of the pelvis. Marcove et al69 successfully
performed an incomplete curettage of the sacrum with cryosurgery in a patient with GCT. Complications, such as extenVOL. 86-B, No. 1, JANUARY 2004
10
M. SZENDRI
Fig. 4a
Fig. 4b
Radiographs showing a) an expansively growing GCT of the innominate bone, and b) after embolisation and curettage of the tumour
followed by reconstruction with PMMA cement and screws. There have been no symptoms for six years.
different percentages of the material, which may have significantly influenced the rate of recurrence. Gitelis et al46
performed en-bloc resection in 50% of their patients and
curettage with adjuvants in the other 50% without observing
any recurrence. In the series of McDonald et al35 curettage
was performed in 80% and the rate of recurrence increased
to 34%.
The management of local recurrence of GCT varies.
Some authors,12,16,85 recommend wide excision for any
recurrent lesion, whereas others24,60 believe that repeated
intralesional surgery with adjuvants for the second or third
recurrence is justified.
Malignant transformation or pulmonary metastases of
benign GCT have been observed after radiotherapy and
after multiple recurrences of a locally aggressive GCT,
especially when the tumour has affected the radius and the
small tubular bones of the hand or feet.38-42,64 Cheng and
Johnston38 collected about 50 published cases of metastasising GCT from the literature with an overall survival rate
of 80% to 85%. Sporadically, spontaneous regression of the
nodules in the lung has been reported,39,45 but the mortality
is about 15% to 20%.39,40 The treatment of choice is the
surgical excision of the nodules.38,41 When this is technically impossible, whole-lung radiotherapy is recommended.87 The effects of chemotherapy are not convincing.
The prognosis of malignant GCT is poor with a five-year
THE JOURNAL OF BONE AND JOINT SURGERY
References
1. Schajowicz F. Histological typing of bone tumours. Berlin: SpringerVerlag, 1993:20-2.
2. Schajowicz F. Tumors and tumorlike lesions of bone and joints. New
York: Springer-Verlag, 1981:220-8.
3. Clohisy DR, Vorlicky L, Oegema TR Jr, Snover D, Thompson RC.
Histochemical and immunohistochemical characterization of cells constituting the giant cell tumor of bone. Clin Orthop 1993;287:259-65.
4. Kito M, Moriya H, Mikata A, et al. Establishment of a cell line from
a human giant cell tumor of bone. Clin Orthop 1993;294:353-60.
5. Komiya S, Sasaguri Y, Inoue A, et al. Characterization of cells cultured
from human giant-cell tumors of bone: phenotypic relationship to the
monocyte-macrophage and osteoclast. Clin Orthop 1990;258:304-9.
6. Roessner A, Vassallo J, Vollmer E, et al. Biological characterization of
human bone tumors: X the proliferation behaviour of macrophages as
compared to fibroblastic cells in malignant fibrous histiocytoma and
giant cell tumor of bone. J Cancer Res Clin Oncol 1987;113:559-62.
7. Gamberi G, Benassi MS, Bohling T, et al. Prognostic relevance of Cmyc gene expression in giant-cell tumor of bone. J Orthop Res
1998;16:1-7.
8. Radig K, Schmider-Stock R, Mittler U, Neumann HW, Roessner A.
Genetic instability in osteoblastic tumors of the skeletal system. Pathol
Res Pract 1998;194:669-77.
9. Masui F, Ushigome S, Fujii K. Giant cell tumor of bone: an immunohistochemical comparative study. Pathol Int 1998;48:355-61.
10. Miyamoto N, Higuchi Y, Tajima M, et al. Spindle-shaped cells derived
from giant-cell tumor of bone support differentiation of blood monocytes to osteoclast-like cells. J Orthop Res 2000;18:647-54.
11. Wulling M, Engels C, Jesse N, et al. The nature of giant cell tumor of
bone. J Cancer Res Clin Oncol 2001;127:467-74.
12. Campanacci M, Giunti A, Olmi R. Giant-cell tumours of bone: a study
of 209 cases with long term follow up in 130. Ital J Orthop Traumatol
1975;1:249-77.
VOL. 86-B, No. 1, JANUARY 2004
11
12
M. SZENDRI
43. Maloney WF, Vangham LM, Jones HH, Ross J, Nagel DA. Benign
metastasizing giant-cell tumor of bone: report of three cases and review
of the literature. Clin Orthop 1989;243:208-15.
44. Schoedel KE, Greco MA, Stetler-Stevenson WG, et al. Expression of
metalloproteinases and tissue inhibitors of metalloproteinases in giant
cell tumor of bone: an immunohistochemical study with clinical correlation. Hum Pathol 1996;27:1144-8.
45. Kay RM, Eckhardt JJ, Seeger LL, Mirra JM, Hok DJ. Pulmonary
metastasis of benign giant cell tumor of bone: six histologically confirmed cases, including one of spontaneous regression. Clin Orthop
1994;302:219-30.
46. Gitelis S, Mallin AB, Piasecki P, Turner F. Intralesional excision compared with en bloc resection for giant-cell tumors of bone. J Bone Joint
Surg [Am] 1993;75-A:1648-55.
47. Kumita SM, Leong PC, Yip K, et al. Vascularized bone grafts in the
treatment of juxta-articular giant-cell tumors of the bone. J Reconst
Microsurg 1998;14:185-90.
48. Labs K, Perka C, Schmidt GR. Treatment of stages 2 and 3 giant-cell
tumor. Arch Orthop Traum Surg 2001;121:83-6.
49. ODonell RKJ, Springfield DS, Motwani HK, et al. Recurrence of
giant-cell tumors of long bones after curettage and packing with cement.
J Bone Joint Surg [Am] 1994;76-A:1827-33.
50. Yip KM, Leung PC, Kumita SM. Giant cell tumor of bone. Clin
Orthop 1996;323:60-4.
51. Blackley HR, Wunder JS, Davis AM, et al. Treatment of giant-cell
tumors of long bones with curettage and bone-grafting. J Bone Joint
Surg [Am] 1999;81-A:811-20.
52. Capanna R, Fabbri N, Bettelli G. Curettage of giant cell tumor of
bone: the effect of surgical technique and adjuvants on local recurrence
rate. Chir Organi Mov 1990;(Suppl):206-8.
53. Frassica FJ, Sim FH, Pritchard DJ, Chao YE. Subchondral replacement: a comparative analysis of reconstruction with methyl-methacrylate or autogenous bone graft. Chir Org Mov (Suppl) 1990;75:
189-90.
54. Leeson MC, Lippitt SB. Thermal aspects of the use of polymethylmethacrylate in large methaphyseal defects in bone. Clin Orthop
1993;295:239-45.
55. Quint U, Mller RT, Mller G. Characteristics of phenol. Arch Orthop
Trauma Surg 1998;117:43-6.
56. Vidal J, Mimran R, Allieu Y, Goalard JM. Plastie de comblement par
mecacrylate de mthyle traitement de certaines tumeurs osseuses
bnignes. Montepellier Chir 1969;15:389-97.
57. Bini SA, Gill K, Johnston JO. Giant cell tumor of bone: curettage and
cement reconstruction. Clin Orthop 1995;321:245-50.
58. Malawer MM, Bickels J, Meller J, et al. Cryosurgery in the treatment
of giant cell tumor: a long-term follow-up study. Clin Orthop
1999;359:176-88.
59. Malawer MM, Dunham W. Cryosurgery and acrylic cementation as
surgical adjuncts in the treatment of aggressive (benign) bone tumors:
analysis of 25 patients below the age of 21. Clin Orthop 1991;262:
42-57.
60. Marcove RC. A 17-year review of cryosurgery in the treatment of bone
tumors. Clin Orthop 1982;163:231-4.
61. Sheth DS, Healey JH, Sobel M, Lane JM, Marcove RC. Giant cell
tumor of the distal radius. J Hand Surg Am 1995;20:432-40.
62. Richardson MJ, Dickinson K. Giant cell tumor of bone. Bull Hosp Jt
Dis 1998;57:6-10.
63. Komiya S, Inoue A. Cementation in the treatment of giant cell tumor.
Arch Orthop Trauma Surg 1993;112:51-5.
64. Athanasian EA, Wold LE, Amadio PC. Giant-cell tumors of the bones
of the hand. J Hand Surg Am 1997;22:91-8.
65. Cheng CY, Shih H-N, Hsu KY, Hsu RWW. Treatment of giant cell
tumour of the distal radius. Clin Orthop 2001;383:221-8.
66. Szendri M. Giant-cell tumor in the radius: aggressiveness and soft-tissue recurrence. Chir Organi Mov 1990;75:241-3.
67. Ben N, Amor H, Zouari M, Karray S, et al. Giant cell tumors of the
distal end of the radius treated by resection-arthrodesis. Acta Orthop
Belg 1998;64:41-6.
68. Ozaki T, Lijenqvist U, Halm H, et al. Giant cell tumor of the spine.
Clin Orthop 2002;401:194-201.
69. Marcove RC, Sheth DS, Brient EW, Huvos AG, Healey JH. Conservative surgery for giant cell tumors of the sacrum: the role of cryosurgery
as a supplement to curettage and partial excision. Cancer 1994;74:
1253-60.
70. Kattapuram AS, ODonnell RJ, Huszar M, et al. Surgical management of innominate giant cell tumor. Clin Orthop 1996;329:281-7.
71. Malone S, OSullivan B, Catton C, et al. Long-term follow-up of efficacy and safety of megavoltage radiotherapy in high-risk giant cell
tumors of bone. Int J Radiat Oncol Biol Phys 1995;33:689-94
72. Schwartz LH, Okunieff PG, Rosenberg A, Suit HD. Radiation therapy in the treatment of difficult giant cell tumours. Int J Radiat Oncol
Biol Phys 1989;17:1085-8.
73. Suit H, Spiro I. Radiation treatment of benign mesenchymal disease.
Semin Radiat Oncol 1999;9:171-8.
74. Bell RS, Harwood AR, Goodman SB, Fornasier VL. Supervoltage
radiotherapy in the treatment of difficult giant-cell tumors of bone. Clin
Orthop 1983;174:208-16.
75. Bennett CJ, Marcus RB, Million RR, Enneking WF. Radiation therapy for giant cell tumor of bone. Int J Radiat Oncol Biol Phys
1993;26:229-304.
76. Antal I, Spi Z, Szendri M. The prognostic significance of DNA cytophotometry and proliferation index (Ki-67) in giant cell tumors of bone.
Orthop 1999;23:315-9.
77. Fornasier VL, Protzner K, Zhang I, Mason L. The prognostic significance of histomorphometry and immunohistochemistry in giant cell
tumours of bone. Hum Pathol 1996;27:754-60.
78. Fukunaga M, Nikaido T, Shimoda T, Ushigome S, Nakamori. A flow
cytometric DNA analysis of giant cell tumors of bone including two
cases with malignant transformation. Cancer 1992;70:1886-94.
79. Krober SM, Greschniok A, Bohm P, Kaiserling E. Giant cell tumor
of bone: morphological, immunohistochemical, morphometric and
DNA flow-cytometric findings. Verh Dtsch Ges Pathol 1998;82:279-83.
80. Antal I, Spi Z, Szendri M. Malignant transformation of giant-cell
tumour in the distal radius: value of the DNA cytophotometry. Ortopde
2000;29:677-83.
81. Bridge JA, Mouron BJ, Neff JR, Bhatia PS. Significance of chromosomal abnormalities in a malignant giant cell tumor of bone. Cancer
Genet Cytogenet 1991;57:87-92.
82. Bridge JA, Neff JR, Bhatia PS, Sanger WG, Murphey MD. Cytogenetic findings and biologic behaviour of giant cell tumors of bone. Cancer 1990;65:2697-703.
83. Rock M. Curettage of giant cell tumor of bone: factors influencing local
recurrences and metastasis. Chir Organi Mov 1990;75(Suppl.1):204-5.
84. Wuismann P, Hrle A, Nommensen B. et al. Giant-cell tumour of
bone: an analysis of 69 cases. Z Orthop 1989;127:392-5.
85. Lausten GS, Jensen PK, Schiodt T, Lund B. Local recurrences in
giant cell tumour of bone: long-term follow up of 31 cases. Int Orthop
1996;20:172-6.
86. Masui F, Ushigome S, Fujii K. Giant cell tumor of bone: a clinicopathologic study of prognostic factors. Pathol Int 1998;48:723-9.
87. Feigenberg SJ, Marcus RB, Zlotecki RA, Scarborough MT, Enneking WF. Whole-lung radiotherapy for giant cell tumors of bone with pulmonary metastases. Clin Orthop 2002;401:202-8.
88. Anract P, De-Piueus G, Cottias P, et al. Malignant giant-cell tumor of
bone: clinical-pathological types and prognosis: a review of 29 cases. Int
Orthop 1998;22:19-26.