Review article
GIANT-CELL TUMOUR OF BONE
M. Szendröi
From Semmelweis University, Budapest, Hungary
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 out-
come; 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 unpre-
dictable. 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 his-
tology.
Pathogenesis
GCT is a true neoplastic process originating from the undif-
ferentiated mesenchymal cells of the bone marrow. Multi-
nucleated 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 mono-
nuclear cells or, less probably, by amitotic division or
nuclear segmentation of the stromal cells without the corre-
sponding cytoplasmic division.2 These multinucleated giant
cells resemble osteoclasts in their phenotype and function:
their size is approximately 60 µm; 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, cyto-
genetic, and molecular-genetic studies in cell cultures
derived from GCTs have confirmed that there are two differ-
M. Szendröi, MD, Professor
Department of Orthopaedics, Semmelweis University, Budapest, Hungary.
Correspondence should be sent to Professor M. Szendröi at H-1113 Buda-
pest, Karolina út, Hungary.
©2004 British Editorial Society of Bone and Joint Surgery
doi:10.1302/0301-620X.86B1.14053 $2.00
J Bone Joint Surg [Br] 2004;86-B:5-12.
VOL. 86-B, No. 1, JANUARY 2004
ent cell lines within the mononuclear stromal cells. One
population consists of mononuclear round cells, which are
non-neoplastic and express monocyte-macrophage markers
(tartrate-sensitive acid phosphatase, naphthyl alpha este-
rase) and react with monoclonal antibodies to CD 13 and
CD 68 which suggests that these cells have a monocytic-
macrophage origin.4-6
The second cell line which appears as mononuclear spin-
dle-shaped (fibro-osteoblast-like) stromal cells is considered
to be responsible for the neoplastic character of the GCT. It
produces type-I and type-II collagens and alkaline phos-
phatase, has receptor sites for parathormone and proliferates
extensively. This cell line is genetically unstable, as has
been found in recent molecular genetic studies. It shows
chromosomal abnormalities, a higher incidence of expres-
sion of p53 protein and alterations in different oncogenes
(C-myc, C-fos, N-myc) which are also found in frankly
malignant osteosarcomas.7,8 These spindle-shaped stromal
cells secrete a variety of cytokines and differentiation fac-
tors (macrophage colony stimulating factor (M-CSF), inter-
feron-gamma (IFN-gamma), tumor necrosis factor alpha
(TNF-alpha)), which have chemotactic, differentiation-
inducing and activating effects on monocytes-macrophages
and are essential for the differentiation of osteoclasts.
These features support the hypothesis that the genetically
unstable spindle-shaped neoplastic mononuclear stromal
cells stimulate the immigration of blood monocytes into the
tumour tissue and promote the formation of the osteoclast-
like giant cells. The characteristic cell types, the monocytes
and osteoclast-like giant cells, are therefore simply reactive
components of the GCT, while the spindle-shaped stromal
cells represent the neoplastic component of the tumour.4,9-11
Clinical appearance
The typical clinical and pathological appearance of GCT
has been discussed in detail in various articles12-18 and
monographs.2,19-21 It represents 15% of benign and 3% to
8% of all bone tumours and is more common in China and
India where it constitutes approximately 20% of all bone
tumours.22 Nearly 50% of cases occur in the region of the
knee, but other frequent sites are the distal part of the radius,
the proximal humerus and fibula, and the pelvic bones. It is
usually situated in the epiphysis, grows eccentrically, and
5
6 M. SZENDRÖI

Table I. The rate of recurrence after different intralesional treatments of

primary GCT of bone (minimum follow-up ≥ 2 years)
Rate of local
Number recurrence
Author/s of patients Adjuvant treatment (%)
Goldenberg et al17 120 None 43
(multicentre)
Campanacci et al12 128 None 30
Capanna et al52 490 None 45
(multicentre)
Lausten et al85 18 None/radiotherapy 56
Richardson and 16 (Burr) none 0
Dickinson62
Blackley et al51 59 Burr, none 12
McDonald et al35 85 Burr, phenol, alcohol 34
Capanna et al52 187 PMMA,* phenol, 17
(multicentre) liquid nitrogen
Szendröi29 11 Phenol, PMMA 9
Komiya and Inoue63 11 Burr, PMMA 0
Gitelis et al46 16 Burr, phenol, alcohol, 0
PMMA
O’Donell et al49 60 PMMA/burr phenol 25
Bini et al57 38 PMMA 8
Malawar and Dunham59 102 (Burr)+liquid nitrogen 7.9
Labs et al48 15 PMMA 12
* polymethylmethacrylate

Fig. 1
Photograph showing the gross pathology of a GCT. The defect in the prox-
imal tibia is filled by extensive soft fleshy tissue and the cortex is destroyed
(surface of transsected specimen).
may later also affect the metaphysis. A GCT starting from
the metaphysis has been described in skeletally immature
patients at an open growth plate.23 It appears most often in
the second to fourth decades of life (60% to 75% of all
cases) and the male:female ratio is 1:1.5.
The main clinical symptoms are non-specific, local
swelling, warmth, and pain radiating independently of
weight-bearing. Pathological fracture is the first sign in
approximately 15% of cases.24 The duration of symptoms
varies between two to six months and by then, in one-third
of cases, the size of the tumour exceeds 50% of the diameter
of the affected bone, it has destroyed the cortical bone and
reached the subchondral region.
GCT appears as a pure lytic cystic lesion, growing often
but not exclusively eccentrically in the epimetaphyseal
region of the bone. The affected part of the bone may be
expanded and the cortical bone thinned. In an advanced
stage, the GCT breaks through the cortex (Fig. 1), and there
is a lack of periosteal reaction with formation of spicules
around the tumour. According to the radiological classifica-
tion of Lodwick, Wilson and Farrel,25 GCT belongs,
depending on its stage, to group IA to IB or IC. GCT is
commonly hypervascularised. With modern MRI, the need
for angiography has been reduced.
CT is useful in the evaluation of the cortical bone. The
density of GCT tissue as measured by CT is between 20 and
70 Housefield units. Below these values a cyst is more likely
those of an aneurysmal bone cyst as has been demonstrated
both by CT and MRI. The MR signs of GCT are a high-
signal intensity in T2-weighted images, high contrast media
enhancement and signs referring to tissue haemorrhages.26
Dynamic contrast-enhanced MRI shows a characteristic
perfusion pattern with a steep slope and maximum intensity
value followed by an early and rapid washout phase.27
Tumours and tumour-like lesions containing giant cells
with a similar radiographic appearance such as juvenile sol-
itary or aneurysmal bone cysts, chondroblastoma, chondro-
myxoid fibroma, giant-cell reparative granuloma, non-
ossifying fibroma, eosinophylic granuloma, high-grade cen-
tral osteosarcoma should be considered in the differential
diagnosis.
There is a high rate of recurrence, especially after intra-
lesional curettage (Table I), in most cases within the first 12
to 36 months,28,29 and rarely after five to six years. The first
symptoms of recurrence are pain and enhanced isotope
uptake by bone scanning.
Grading and staging systems for GCT
Based on the degree of histological appearance of the stro-
mal cells and the number of giant cells and mitoses, Jaffe et
al,18 classified GCT as benign, aggressive and malignant.
Dahlin19 distinguished only benign and malignant forms of
GCT. The grade-3 malignant GCTs should be treated as
high-grade bone sarcomas otherwise the practical value of
grading is limited. The prediction of the clinical behaviour
of GCT based on its histological features is impossible.2,30
Enneking20 and Campanacci et al12 developed a similar
classification for GCT based on their clinical, radiographic
and histological features. Enneking’s surgical stages 1, 2
THE JOURNAL OF BONE AND JOINT SURGERY
 GIANT-CELL TUMOUR OF BONE
Fig. 2a
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.
and 3 represent the clinically latent, active and aggressive
forms of GCT. The radiographic grade-1 of Campanacci et
al12 represents a quiescent form, in which the cortical
involvement is minimal, if at all. Only 10% to 15% of GCTs
belong to this rare stage which can even be asymptomatic.
The most common active grade-2 lesions show extensive
cortical thinning and bulging. The aggressive grade-3
lesions break through the cortical bone and have a soft-
tissue component covered by a pseudocapsule and perios-
teum. On rare occasions, the tumour extends its barrier, the
articular cartilage, and enters the joint.
Although Campanacci nominates this latter group of
GCT as malignant, the term ‘aggressive’ is more justified
because in most cases this tumour has a benign histology
and can be cured by conservative surgery, namely curettage.
This final stage has, however, a greater risk of local recur-
rence.
Special forms of GCT
GCT is typically a monostotic process, but multicentric
(polyostotic) forms have been described occasionally.31,32
This rare condition can appear simultaneously or
metachronal33 with an interval of more than ten years. A
direct, continuous extension of GCT from one bone to the
next (Fig. 2), which occurs mostly in the short bones of the
hand and feet,34 should be excluded.
A rare form is the malignant GCT, which can be divided
into primary and secondary groups. The primary form (1%
to 3% of all GCTs)16,35 is malignant from the onset.
VOL. 86-B, No. 1, JANUARY 2004
7
Fig. 2b
Frankly sarcomatous stroma is juxtaposed to areas of typi-
cal 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 fre-
quency of finding tumour emboli in vessels and that of pul-
monary involvement. Recent basic studies have shown
enhanced matrix metalloproteinases, expression of p53 pro-
tein and overexpression of the C-myc oncogene in metasta-
sising 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 pres-
entation 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
8 M. SZENDRÖI
Fig. 3a
Fig. 3c
resection, the rate of the recurrence is between 0% and 5%
in primary lesions.46-50 Because it is found in the epiphysis,
the GCT often invades the subchondral bone. En-bloc resec-
tion usually requires sacrifice of the articular surface and a
complex reconstruction procedure, which can lead to com-
plications, revision operations, and decreased quality of life
in the long term.
Fig. 3b
GCT in the distal part of the radius. Figure 3a – Radio-
graph showing the lytic lesion with an ill-defined bor-
der to normal bone. Figure 3b – MRI showing a high
signal on the T2-weighted image, representing
necrotic areas in the tumour tissue. Figure 3c – Radio-
graph showing en-bloc resection of the tumour and
transposition of the fibular autograft. There have been
no symptoms for four years.
Resection is usually performed in GCTs found in the
proximal fibula, radius, distal ulna or in the wing of the
ilium in which a reconstruction is not necessary, or in malig-
nant types of GCTs. Stage-3 GCTs, which have already
destroyed the cortex tend to recur more often and when the
defect is large and the joint surface destroyed, resection is
indicated. We try to preserve the joint even in a stage-3
THE JOURNAL OF BONE AND JOINT SURGERY
 GIANT-CELL TUMOUR OF BONE
lesion, taking into account the higher probability of recur-
rence. 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 intro-
duced. These presumably remove the tumour cells which
remain after curettage because of their thermal (liquid nitro-
gen, methylmethacrylate) or chemical (phenol, hydrogen-
peroxide, 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 curet-
tage 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 diffi-
cult 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 histori-
cal 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 high-
speed 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 recom-
mended 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 non-
vascularised (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 peri-
acetabular region of the pelvis. Marcove et al69 successfully
performed an incomplete curettage of the sacrum with cryo-
surgery in a patient with GCT. Complications, such as exten-
VOL. 86-B, No. 1, JANUARY 2004
9
sive intra-operative bleeding, can be avoided by embolisation
of the supplying arteries in huge GCTs of the innominate
bone (Fig. 4). Kattapuram et al70 recommended combined
surgery and radiotherapy for GCT located in the pelvis.
Radiotherapy. Three to four decades ago, radiation of
aggressive GCT with appendicular, pelvic, sacral and spinal
lesions was commonly undertaken. Orthovoltage equipment
was used but the bone and tumour dosimetry was poor,
since doses below 35 Gy were given. The results were dis-
appointing. The rate of local recurrence was between 50%
and 70%. Malignant transformation14,17,36 occurred in 7%
to 25% of the irradiated GCT.
According to some reports,71-73 the use of modern equip-
ment (supervoltage therapy,60Co or linear accelerator), and
doses of 40 to 60 Gy (1,8 - 2,0 Gy/fraction, 3 to 5 times/
week) can result in local oncological control of 85% to
90%. The risk of secondary radiation-induced malignant
tumour is very small (0% to 8%).71,74,75
In selected cases, therefore, if curettage is only incom-
plete (pelvis, vertebra, etc) resection will result in signifi-
cant neurological or functional morbidity (sacral lesions).
Radiation is an effective alternative.
Prognosis and final outcome. The evaluation of prognostic
factors is difficult for various reasons. GCT is relatively
rare,2 and there are only a few multicentre studies which
have described a large number of cases, the indications,
treatment philosophy and statistical methods used vary and,
there is a lack of prospective, randomised studies. A number
of publications deal, however, with potential prognostic fac-
tors which may influence or predict the recurrence and
malignant transformation of GCT.
The histological grading has little prognostic
value.14,17,30,42 The benign or malignant nature of the
tumour can be determined. Benign histology does not nec-
essarily relate to the clinical behaviour of the tumour.
Immunohistological and cytogenetic examinations give
additional information which may be useful. There is a rela-
tionship, for example, between the increasing rate of prolif-
eration and the probability of recurrence.30,76,77 The value
of flow cytometry is disputed.78,79 Our results with smear
cytometry which allows separate examination of the stromal
cell population showed a significant difference in the ploid-
ity of non-recurring and recurring GCTs during follow-up
studies. Two-thirds of non-recurring GCTs were character-
ised by euploidity and most of the recurrence GCTs by ane-
uploidity.76,80
Bridge et al81,82 found that all but one of their recurrent
GCTs had some type of chromosomal abnormality, which
could also be detected in highly malignant osteosarcomas.
Schoedel et al44 demonstrated an excessive metalloprotein-
ase expression in recurrent or metastasising GCTs, which is
also found in the degradation of extracellular matrix and in
tissue invasion. An overexpression of c-myc oncogen32 and
p539 was found in GCTs metastasising to the lung.
The clinicoradiological staging systems of Enneking20
and Campanacci et al12 and their prognostic significance
10
Fig. 4a
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.
are also disputed. Rock83 and Wuismann et al84 observed a
sequential increase in local rates of recurrence from stage
1 through to stage 3. However, many authors, including
ourselves, do not regard these staging systems as predic-
tive of the prognosis.13,38,76,85,86 Most GCTs show a ten-
dency to progress and without treatment they reach stage 3
sooner or later, as we have seen in many cases of retro-
spective analysis of radiographs of untreated patients
(Fig. 2). In Rock’s series,83 however, the 16 patients with
metastases had an equal distribution between stages 2
and 3.
McDonald et al35 analysing the data of 221 patients with
GCT did not find any correlation between the rate of recur-
rence and the size, localisation, the surgical stage of the
tumour and involvement of the subchondral bone. Patho-
logical fracture in itself does not significantly increase the
risk of recurrence.24,83 The most significant factor is the
surgical procedure employed for removal of the tumour i.e.,
curettage with adjuvant therapy (34% recurrence) versus
resection (7% recurrence). This observation has been con-
firmed by many others authors.46-48,85
When evaluating the results of the very different surgical
methods, there is a lack of prospective randomised studies
comparing the effects of the adjuvants with the results of
curettage using a high-speed burr and bone grafting alone.
In addition, resection and curettage have been performed in
M. SZENDRÖI
Fig. 4b
different percentages of the material, which may have sig-
nificantly 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 metasta-
sising 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 techni-
cally impossible, whole-lung radiotherapy is recom-
mended.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
 GIANT-CELL TUMOUR OF BONE
survival of 50%,88 despite the combination of surgery and
chemotherapy.
Malignant transformation occurs, however, only in 5% to
10%, with pulmonary metastases in another 2% to 6%.
According to the results of larger series, most authors report
a disease-free survival of 96% to 100% as the final outcome
of the treatment.15,46,49,51,83
Recurrence of GCT is not fatal in most cases, but can
lead to disability and to a poor quality of life as a result of
repeated and radical operations, loss of bone stock, and sec-
ondary arthritis of the joints. Optimal treatment should
include: 1) careful curettage and the use of adjuvants to
decrease the rate of recurrence; 2) joint-sparing surgery at
revision operations and in stage-3 tumours whenever it is
possible; 3) in cases of proven malignancy: resection
according to oncological criteria; and 4) comparative histo-
logical and molecular biological evaluation of the primary
and recurrent tumours. In the future, histochemistry, DNA
cytometry, examination of the expression of certain onco-
gens, proteins, cytokines and the quantitative-qualitative
measurement of molecular genetic instability of the tumour
will have a greater influence on the surgical planning.
Because of the relative rarity of the tumour and the spe-
cial operative techniques involved, it is recommended that
GCT be treated in tumour clinics. Inadequate primary inter-
vention by a non-specialist can lead to major technical chal-
lenges at an advanced stage of the tumour.
This paper is based on an Instructional Course Lecture. European Instruc-
tional Course Lectures, Vol. 6, 2003, 89-98.
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