Current Diagnostic Pathology (2001) 7, 235d246

^ 2001 Harcourt Publishers Ltd

doi:10.1054/cdip.2001.0080, available online at http://www.idealibrary.com on

MINI-SYMPOSIUM: BONE TUMOURS

Giant cell containing lesions of bone and their

differential diagnosis
A. E. Rosenberg and G. P. Nielsen
James Homer Wright Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

KEYWORDS
bone tumour, giant cell,
brown tumour, giant cell
tumour, giant cell
reparative granuloma,
non-ossifying fibroma,
aneurysmal bone cyst,
chondroblastoma,
osteosarcoma

Summary Giant cell rich lesions encompass a relatively large group of biologically and
morphologically diverse bone tumours. They are all related to one another by the
presence of numerous multinucleated osteoclast-like giant cells. However, they differ
from each other by virtue of their clinical and radiographic characteristics and in many
cases, their morphology. In select cases, immunohistochemistry may be necessary to
make an accurate diagnosis. The importance of correctly identifying these tumours rests
on the differences in their treatment and prognosis. ^ 2001 Harcourt Publishers Ltd

INTRODUCTION
Giant cell rich lesions of bone represent a group of
morphologically and biologically diverse tumours of the
skeleton (see Table 1). Common to all of them are
innumerable non-neoplastic osteoclast-like giant cells
that are an inherent component of the tumour. The
key to distinguishing amongst these tumours is their
distinctive clinical and radiographic characteristics and,
most importantly, the histological features of the cell
type(s) other than the giant cells. This article will discuss
the more common reactive lesions, and benign and
malignant neoplasms that comprise the family of giant cell
lesions of bone.

NON-NEOPLASTIC LESIONS
Brown tumour of hyperparathyroidism
Brown tumours are masses of non-neoplastic reactive
tissue and develop as a complication of hyperparathyroidism. In fact, it is the haemorrhage and haemosiderin
deposits that are found within them that give the lesion
its brown colour, for which it has been named. The
association of a brown tumour with a parathyroid
adenoma was first noted by Askanazy in 1904, and

Correspondence to: AER. Tel: #1-617-7265127; Fax: #1-617-7269312; E-mail: arosenberg@partners.org

subsequently, brown tumours have been documented to

arise in the setting of primary, secondary and tertiary
hyperparathyroidism. They usually develop in adults who
are in their third and fourth decades of life and females
are affected more frequently than males. Brown tumours
may be solitary or multiple and commonly arise in the
pelvis, ribs, clavicles and extremities. Atypical locations
include the sphenoid sinus,1 vertebral column2 and
cricoid cartilage.3 Clinically, they may produce a mass
that can be painful.
Brown tumours manifest radiographically as expansile,
lytic lesions with occasional intralesional trabeculations
(Fig. 1). The surrounding periosteum produces reactive
bone and the margins of the tumour may be well defined
or indistinct. Other radiographic characteristics of
hyperparathyroidism including generalized osteoporosis,
subperiosteal bone resorption of the distal phalanges,
pelvis and clavicle and diffuse granular radiolucencies in
the skull are also frequently present. The radiographic
differential often includes metastatic disease and multiple
myeloma.
Grossly, brown tumours are well-circumscribed,
reddish brown, haemorrhagic masses. Histologically,
they have a lobular architecture produced by fibrous
septae that may contain trabeculae of reactive woven
bone (Fig. 2). The lobules are composed of an admixture of plump fibroblasts, extravasated red blood
cells, haemosiderin-laden macrophages and scattered
osteoclast-type giant cells, which frequently cluster
around areas of haemorrhage (Fig. 3). This bloody mass
of reactive tissue erodes the endosteum, resulting in

236

CURRENT DIAGNOSTIC PATHOLOGY

Table 1 Giant cell lesions of bone

Reactive

Benign

Malignant

Brown tumour
Haemophiliac pseudotumour
Intraosseous haemorrhage

Giant cell reparative granuloma

Non-ossifying fibroma
Giant cell tumour
Aneurysmal bone cyst (ABC)
Chondroblastoma
Chondromyxoid fibroma
Langerhans cell histiocytosis
Pigmented villonodular synovitis

Osteosarcoma
Malignant fibrous histiocytoma
Clear cell chondrosarcoma
Metastatic carcinoma

Figure 3 Brown tumour composed of fibroblasts, osteoclastlike giant cells and extravasated red blood cells.
Figure 1 Axial CT of brown tumour in a rib. The tumour is
well demarcated, expands the bone, and has a lobular configuration.

Figure 2 Brown tumour compartmentalized by septae containing reactive bone.

thinning and expansion of the cortex as the periosteum

deposits new bone. In severe cases, large blood-filled
cysts develop and the resultant lesion is known as osteitis
fibrosa cystica. Areas of bone uninvolved by the tumour

show evidence of increased osteoclastic activity in

the form of dissecting osteitis (osteoclasts boring
through the centre of bony trabeculae), cortical
cutting cones (groups of osteoclasts tunnelling into
and expanding Haversian canals) and subperiosteal
excavation.4 Treatment of the underlying abnormality
abates the osteoclastic activity and the lesion
eventually regresses as it is filled in by newly deposited
bone.
The histological differential diagnosis of brown tumour
includes other giant cell rich lesions especially giant cell
reparative granuloma (GCRG) and giant cell tumour of
bone. GCRG can have very similar morphological
features and may be impossible to distinguish from
brown tumour by light microscopy alone. We have
noted that brown tumours have a much more lobulated
architectural growth pattern than giant cell reparative
granuloma. In the diagnostic areas of giant cell tumour
of bone, the mononuclear cells are not as spindled
as the fibroblasts in brown tumour and the nuclei of
the mononuclear cells are morphologically identical
to those in the osteoclasts which is not a finding in
brown tumour.

GIANT CELL CONTAINING LESIONS OF BONE AND THEIR DIFFERENTIAL DIAGNOSIS

BENIGN NEOPLASMS
Giant cell tumour
Giant cell tumour of bone is the prototype of giant cell
rich neoplasms of the skeleton. The term giant cell
tumour was coined by Bloodgood in 19125 and it was not
until 1940 that Jaffe distinguished giant cell tumour of
bone from other bone tumours containing many
osteoclast-like giant cells.6 Giant cell tumour of bone
accounts for approximately 4}5% of all primary bone
tumours and in the Mayo Clinic experience it represents
almost 23% of benign skeletal neoplasms examined
histologically.7}10
Giant cell tumour of bone is defined pathologically as
a neoplasm composed of cytologically benign, oval or
polyhedral mononuclear cells that are admixed with
numerous, evenly distributed, osteoclast-like giant cells.
The exact phenotype of the mononuclear cells is not
clear and evidence has suggested that they may be
undifferentiated mesenchymal cells, fibroblasts or
macrophages.
Giant cell tumour of bone frequently produces pain
and usually develops during the third to fifth decades of
life; they rarely arise in children.11 In many series females
are affected slightly more frequently than males in a ratio
of 1.2 : 1.10 The vast majority of giant cell tumours of

Figure 4 Plain X-ray of giant cell tumour of distal radius. The

tumour is eccentric, lytic, spans the epiphysis and metaphysis, and
has destroyed the cortex and extended into the soft tissues.

237

bone arise in the epiphyseal}metaphyseal region of long

tubular bones.7}10 Almost one-half of cases develop
about the knee, especially in the distal femur followed by
the proximal tibia; the third most common location is the
distal end of the radius. Uncommon sites of involvement
include the vertebral bodies, small tubular bones of the
hands and feet and the patellae. Giant cell tumours are
usually solitary but in (1% of cases they are multifocal
and in such cases the hands and feet are frequently
affected.12
Radiographically, giant cell tumour of bone manifests
as an eccentric, large, lytic mass that frequently extends
from the subchondral bone plate into the metaphysis;
larger tumours may involve the adjacent diaphysis or
invade the neighbouring soft tissues (Fig. 4).7,10,13 The
tumour often expands the bone with varying amounts
of cortical destruction. Although the margins are well
defined, they are usually not sclerotic and in some cases
they may even be motheaten. Cystic degeneration is
a common secondary change.
Grossly, giant cell tumours are friable, haemorrhagic,
red}brown masses that are solid or focally cystic and
typically range in size from 5 to 15 cm in greatest
dimension. They erode the cortex and have welldelineated margins within the medullary canal and
neighbouring soft tissues. The histological hallmark of
giant cell tumours is the innumerable multinucleated
osteoclast-like giant cells that are scattered evenly
throughout the tumour (Fig. 5). The number of nuclei in
any individual cell is variable but may be as many as 50 or
more. The nuclei are oval, vesicular, have central nucleoli
and tend to be situated in the centre of the cell where
they are surrounded by abundant eosinophilic cytoplasm.
The round or oval mononuclear stromal cells are the
diagnostic and neoplastic component of the tumour.
These cells appear to grow in a syncytium and have little
cytoplasm and ill-defined cell borders. The nuclei are
round or oval, vesicular, have central nucleoli and are

Figure 5 Giant cell tumour composed of syncytium of mononuclear cells admixed with many osteoclast-like giant cells.

238

Figure 6 Tissue from periphery of giant cell tumour composed of fibroblasts arranged in a storiform pattern with scattered
osteoclast-like giant cells.

morphologically identical to the nuclei of the giant cells

(Fig. 5). The mononuclear cells may be mitotically active
and can show varying degrees of cytological atypia, which
may be especially prominent in areas adjacent to
previous haemorrhage and fibrin deposition. Areas of
necrosis and vascular invasion may also be present. Most
giant cell tumours also have regions that morphologically
resemble benign fibrous histiocytoma or non-ossifying
fibroma (Fig. 6). These regions are characterized by
cytologically banal spindle cells arranged in intersecting
fascicles forming a storiform pattern with osteoclast-like
giant cells scattered about in smaller numbers. This
spindle cell component is frequently located in the
periphery of the tumour and in and of itself is not
diagnostic of giant cell tumour. However, in the
appropriate clinical setting it is strongly suggestive of
the diagnosis. Other secondary changes commonly
encountered in giant cell tumour include haemosiderin
deposits, aggregates of foamy macrophages, cystic
change and reactive bone formation.
Ultrastructurally, abundant dilated rough endoplasmic
reticulum, well-developed Golgi apparatus, mitochondria
and occasional lipid droplets are the prominent features
in the cytoplasm of the mononuclear cells.14 The
multinucleated giant cells have features similar to
osteoclasts. Immunohistochemically, the mononuclear
cells express vimentin and alpha-1-antitrypsin and do
not stain with antibodies to S-100.15 The giant cells
have an immunoprofile similar to that of macrophages.
These findings have suggested that the mononuclear
and multinucleated cells in giant cell tumour are
of histiocytic derivation. However, the controversy
over the phenotype of giant cell tumour has not been
resolved.
Cytogenetic studies have shown that the most
common chromosomal aberration of giant cell tumours
is telomeric associations.16 The significance of this finding
is unknown.

CURRENT DIAGNOSTIC PATHOLOGY

Biologically, giant cell tumours of bone are considered
benign neoplasms. They are usually treated by curettage
and less frequently by en bloc resection. Radiation is
used on tumours that cannot be resected because of
their location or if the patient has significant medical
problems.17 The local recurrence rate is approximately
25% for patients treated with curettage and most
recurrences are detected within 3 yr after initial
therapy.18 Although giant cell tumours are classified as
being benign, it is well recognized that 1}2% of them
eventually metastasize, mainly to the lung. These patients
are frequently cured by resection of the pulmonary
nodules. Another dreaded but uncommon complication
of giant cell tumour is the development of a sarcoma.
This may occur de novo, develop in a local recurrence or
following radiation of the tumour.
The histological differential diagnosis of giant cell
tumour of bone includes many of the lesions in Table 1.
Its most important distinguishing histological feature is
the morphological identity of the nuclei in the mono- and
multinucleated cells.

Giant cell reparative granuloma

(giant cell granuloma)
The term giant cell reparative granuloma (GCRG) was
initially coined by Jaffe in 195319 to describe a tumour of
the jaw bones that had previously been diagnosed as
giant cell tumour of bone.20 In 1962, Ackerman and Spjut
described the first two cases involving the small tubular
bones of the hand, for which they coined the term giant
cell reaction.21 Subsequently, most reports have shown
that GCRG is limited to these two anatomical sites.
The majority of GCRG that arise in the jaw bones
occur in the first and second decades of life and are
approximately twice as common in females as in
males.22,23 Clinically, the patients complain of swelling,
pain or displacement of teeth. It is also not uncommon
for these lesions to be incidentally discovered on X-rays
taken for other reasons. Patients with GCRG involving
the small tubular bones of the hand and feet are older
with the peak incidence in the second to third decades.24
Signs and symptoms in this location are similar with
patients complaining of pain and swelling occasionally
secondary to a pathological fracture. GCRG very rarely
involves other bones and there have been rare cases of
GCRG involving multiple sites.25
As the name implies, and as Jaffe believed, GCRG is
thought to be a non-neoplastic, reparative or a reactive
process. The term GCRG is misleading as it does not
contain true granulomas. Therefore, the non-committal
designation giant cell lesion has been recommended by
some authors.20 Although GCRG is believed to be
a reactive/reparative process, there is frequently no
history of trauma. However, it is possible that previous

GIANT CELL CONTAINING LESIONS OF BONE AND THEIR DIFFERENTIAL DIAGNOSIS

Figure 7 Plain X-ray of giant cell reparative granuloma. The

anterior mandible is distorted by a multinodular lytic mass that has
well-defined margins.

trauma may have been forgotten or that the traumatic

episode precedes the appearance of GCRG by many
years.22 It has been also hypothesized that the giant cell
rich areas represent a reaction to recent haemorrhage
and the fibroblastic component represents the older or
the healing part of the lesion.22 Recently, cytogenetic
abnormalities have been identified in a GCRG raising the
possibility that this tumour may indeed be neoplastic
after all.26
Within the head and neck region, GCRG characteristically arises in the mandible and less commonly in the
maxilla. It has a tendency to involve the anterior portions
of these bones and usually does not extend posterior to
the first permanent molar area. GCRG rarely affects
other bones of the skull.22,23 In the small bones of the
hand and feet it can involve the phalanges, metacarpals
and metatarsals and the carpal and tarsal bones.24,27
Radiographically, in the craniofacial bones, GCRG
forms a well-demarcated, radiolucent, often trabeculated
or multiloculated (soap bubble) lesion that may expand
the bone (Fig. 7).19,28 The multiloculated appearance is
more common in large tumours. Adjacent teeth are
more frequently displaced rather than resorbed.29 The
cortex is usually intact and there is no periosteal
reaction.30 In the small tubular bones of the hand and
feet, GCRG can involve the diaphysis, metaphysis,
epiphysis or the entire length of the bone, where it forms
a radiolucent, expanding lesion with no evidence of
cortical destruction.
Grossly, the tumour is red}brown and haemorrhagic.
Microscopically, it consists of spindled fibroblasts that
are admixed with collagen, areas of haemorrhage and
numerous multinucleated osteoclast-type giant cells
(Fig. 8). The giant cells tend to be arranged in small
clusters. They contain fewer nuclei than seen in
conventional giant cell tumour of bone, and are almost
always associated with areas of haemorrhage. Addi-

239

Figure 8 Giant cell reparative granuloma composed of fascicles of fibroblasts with osteoclast-like giant cells clustering
around a focus of haemorrhage.

tionally, scattered lymphocytes, haemosiderin deposits

and reactive woven bone rimmed by osteoblasts and
small blood-filled spaces (aneurysmal bone cyst-like
areas) are frequently present.22 Mitotic figures are usually
few in number.
The treatment for GCRG is curettage, after which the
lesion usually heals and becomes ossified.31,32 The tumour
can locally recur; however, it is uncommon for it to
recur after the second curettage.24,27,31,33}35 In surgically
inaccessible lesions such as the skull base, partial removal
of the lesion, combined with radiation therapy may be
indicated.22,34,35
The histological differential diagnosis includes a variety
of bone lesions that contain osteoclast-type giant cells.
Morphologically, GCRG is indistinguishable from brown
tumour of hyperparathyroidism, and Jaffe in his original
description believed that brown tumour of hyperparathyroidism 2also represents a giant-cell reparative
granuloma.19 Every patient with GCRG should therefore
have the appropriate tests to rule out hyperparathyroidism. The jaw lesions present in patients with
Jaffe}Companacci syndrome ( JC) (multiple non-ossifying
fibromas, cafeH -au-lait skin lesions, and other extraskeletal
anomalies) are also histologically similar to GCRG,36 and
the possibility of JC syndrome should always be kept in
mind in a patient with multiple jaw lesions. Another
tumour in the differential diagnosis is conventional giant
cell tumour of bone. Unlike GCRG, the osteoclast-type
giant cells in giant cell tumour of bone contain more
nuclei than the giant cells in GCRG, and the nuclei in the
giant cells are morphologically identical to those of the
stromal cells. Another feature helpful in this distinction is
the distribution of the giant cells. In GCRG, the giant cells
cluster around areas of haemorrhage, whereas in giant
cell tumour of bone they are evenly distributed
throughout the tumour. The solid variant of aneurysmal
bone cyst37 is also histologically identical to GCRG and it
is possible that they represent the same or similar

240

CURRENT DIAGNOSTIC PATHOLOGY

lesions. Although recent cytogenetic data in conventional

aneurysmal bone cyst have shown different cytogenetic
abnormalities38 we are not aware of any cytogenetic
studies done on solid aneurysmal bone cyst.

Non-ossifying fibroma
(fibrous cortical defect)
Non-ossifying fibroma, also known as metaphyseal
fibrous defect, is considered to be a non-neoplastic
process, probably related to a defect in ossification. It
classically involves the metaphysis, which is the growing
portion of long tubular bones, in skeletally immature
individuals. The term fibrous cortical defect can be applied to the lesion when it is confined to the cortex but
if the lesion enlarges and extends into the adjacent
medullary cavity the apellation non-ossifying fibroma is
more appropriate.39
Most non-ossifying fibromas are single but occasionally
patients can be found to have multiple lesions. These
multifocal non-ossifying fibromas can be associated
with rare syndromes such as neurofibromatosis (von
Recklinghausens disease) and JC syndrome.
Patients are usually in their second decade of life at the
time of diagnosis. The distal femur, proximal tibia and
distal tibia are most frequently affected; rarely are the flat
or short tubular bones involved.10 Radiological studies
have shown that non-ossifying fibroma can be seen in
30}40% of skeletally immature individuals.10,39 The fact
that non-ossifying fibroma is rarely seen in adults
suggests that it eventually undergoes spontaneous
resolution in most patients.40 This is supported by the
classic study by Sontag et al,41 who followed 200 children
with periodic radiographs. At the average age of 4 yr,
many children showed a lesion involving the cortex,
which was found in 54% of boys and 22% of girls. The
lesions regressed spontaneously over an average time
of approximately 2.5 yr. Most non-ossifying fibromata
are asymptomatic and are discovered incidentically on
X-rays taken for other reasons. Larger lesions can cause
pain that is probably secondary to microfractures or
more obvious pathological fractures.40,42
Radiographically, classic non-ossifying fibroma forms
a lytic lesion centred within the metaphyseal cortex of
long tubular bones (Fig. 9). It is well demarcated with
a sclerotic margin and frequently shows internal
trabeculations. The trabeculations are incomplete and
are the result of scalloping of the affected cortex. As the
individual grows, the lesion becomes incorporated into
the adjacent diaphysis and if it regresses it undergoes
sclerosis. The radiographic features of this lesion are
so characteristic that in most instances a biopsy is not
indicated.
Grossly, the tumour is eccentric and cortically located,
well demarcated and has sclerotic borders. The overlying

Figure 9 Plain film of non-ossifying fibroma showing an eccentric, lytic mass with sclerotic margins in the metaphysis of the distal
tibia.

Figure 10 Non-ossifying fibroma characterized by cellular fascicles of spindle cells arranged in a storiform pattern with scattered osteoclast-like giant cells.

cortex is attenuated but intact. The lesion is tan-brown

and frequently has areas of yellow discolouration. Cystic
changes (aneurysmal bone cyst-like areas) can be seen
and areas of haemorrhage and necrosis can also be seen
secondary to pathologic fracture. Microscopically, the
most prominent cell type in non-ossifying fibroma are
spindle-shaped fibroblasts that are arranged in a storiform
growth pattern (Fig. 10). Scattered throughout the lesion
are osteoclast-type giant cells and chronic inflammatory
cells. Other secondary changes include haemosiderin
deposits and collections of foamy histiocytes.

GIANT CELL CONTAINING LESIONS OF BONE AND THEIR DIFFERENTIAL DIAGNOSIS

Asymptomatic lesions do not need surgical treatment.
Larger lesions that are painful or have an impending or
established pathological fracture, should be treated by
curettage.
A variety of lesions enter into the histological
differential diagnosis; however, when the patients age
and radiographic findings are correlated with the histological findings the diagnosis should be straightforward.
The occasional giant cells in non-ossifying fibroma
frequently result in its being misdiagnosed as a giant cell
tumour of bone. However, the clinical and radiographic
findings of these two tumours are distinctively different.
Furthermore, in the diagnostic areas of giant cell tumour,
the morphology of the nuclei in the giant cells is identical
to that of the mononuclear stromal cells, a finding not
present in non-ossifying fibroma.

241

Figure 12 Axial MRI of aneurysmal bone cyst showing characteristic fluid}fluid levels.

Aneurysmal bone cyst

Aneurysmal bone cyst (ABC) is a benign tumour of bone
that was first described by Jaffe and Lichtenstein in
1942.43 It is a destructive, expansile lesion characterized
by multiloculated blood-filled cystic spaces. Despite
its aggressive radiographic appearance, ABC behaves
in a benign fashion and it is uncertain whether it is
a neoplasm or a reactive process, the former hypothesis
being supported by recent cytogenetic studies.38,44}47
ABC affects all age groups but generally occurs during
the first two decades of life and has no sex
predilection.46,48 It most frequently develops in the
metaphyses of long bones and the posterior elements of
vertebral bodies.48 The most common signs and
symptoms are pain and swelling, rarely secondary to
a pathological fracture. When ABC involves the
vertebrae it can compress nerves and cause neurological
symptoms.

Figure 11 Radiograph of an aneurysmal bone cyst of the distal

end of the clavicle producing an expansile, lytic mass. Periosteal
shell of bone is focally present.

Figure 13 Aneurysmal bone cyst with numerous cyst spaces

filled with blood.

Radiographically, it is usually an eccentric, expansile

lesion with well-defined margins (Fig. 11). Most lesions
are completely lytic and often contain a thin shell
of reactive bone at the periphery.44,46,48 Computed
tomography and magnetic resonance imaging may
demonstrate internal septa and characteristic fluid}fluid
levels (Fig. 12).44,48
Grossly, ABC is multiloculated, consisting of multiple
blood-filled cystic spaces separated by thin tan-white
septa. More solid tan-white areas can also be seen and
they may either represent a solid portion of the ABC or
a primary lesion, which has undergone ABC-like change.
These areas therefore need to be thoroughly sampled to
identify a primary lesion, if present. Histologically, ABC
is composed of blood-filled cystic spaces separated by
fibrous septa (Fig. 13). The fibrous septa are composed
of plump uniform fibroblasts, multinucleated osteoclasttype giant cells, and reactive woven bone (Fig. 14). The
reactive woven bone is lined by osteoblasts and its

242

CURRENT DIAGNOSTIC PATHOLOGY

coma. Although telangiectatic osteosarcoma can grossly
simulate ABC on microscopic examination, the fibrous
septa in telangiectatic osteosarcoma reveal marked
pleomorphism and easily identified mitotic figures
including those that are atypical.

Chondroblastoma

Figure 14 Cyst wall of aneurysmal bone cyst composed of

reactive fibrous tissue, woven bone and osteoclast-like giant cells.

deposition follows the contours of the fibrous septa.

Approximately, one-third of cases contain a cartilage-like
matrix, also known as blue bone, which is infrequently
seen in other bone lesions.36,48 Mitoses can be seen
within the fibrous septa. However, it is uncommon to
see necrosis unless there has been a previous
pathological fracture. ABC may arise de novo (primary
ABC), or areas resembling ABC can be found in other
benign and malignant bone tumours (secondary ABC)
that have undergone secondary cystic change.46 In these
instances, it is obviously important to recognize the
underlying benign or malignant condition as that process
dictates the behaviour and treatment of the tumour.
Primary ABCs account for approximately 70% of
cases.46 The majority of secondary ABCs arise in
association with a benign neoplasm, most commonly
giant cell tumour of bone or an osteoblastoma.44,46,48 In
1983, Sanerkin et al37 described an unusual non-cystic
intraosseous lesion that had the morphological features
that can be found in the more solid areas of ABC and
they termed this tumour the solid variant of aneurysmal
bone cyst. Their four patients were 5}13-years old; three
tumours arose in the spine and one in the ethmoid bone.
Histologically, the solid variant of ABC is very similar if
not identical to GCRG, and as previously discussed it is
unclear whether GCRG and pure solid ABC are the
same entity or not. Although ABC has been considered
a non-neoplastic process, recent studies have shown
that it manifests reproducible clonal chromosomal
abnormalities, suggesting that it may be neoplastic in
nature.49
The treatment for ABC is surgery, usually in the form
of curettage or in certain situations en bloc resection.
The recurrence rate is low and sometimes spontaneous
regression has followed incomplete removal. Rare
reports of apparent malignant transformation of an ABC
have been described.50 The differential diagnosis includes
all entities that may show secondary ABC-like changes,
GCRG and most importantly telangiectatic osteosar-

Chondroblastoma is an uncommon, painful, benign

cartilage tumour. It accounts for (1% of all primary
bone tumours and the Mayo Clinic found that it
represents 4.7% of their benign bone tumours. Kolodny
and Ewing described chondroblastoma as early as 1927
and 1928, respectively, and both considered it a variant
of giant cell tumour.51 Codman in 1931, was the first to
consider it a specific clinicopathological entity and
designated it an epiphyseal chondromatous giant cell
tumour, and Jaffe and Lichtenstein coined the term
chondroblastoma in 1942.52,53
Chondroblastoma is one of the few bone tumours that
almost always arises in the epiphysis or an apophysis
(epiphyseal equivalent).10,51,54,55 Although it can originate
in any bone, slightly more than one-half of cases develop
in long tubular bones with the femur most frequently
affected followed in descending order by the tibia and
humerus. Approximately 23% of cases involve the bones
of the hands and feet and 16% arise within the pelvis.54
Most patients are young at the time of diagnosis with 4%
in the first decade, 54% in the second decade, 24% in the
third decade and 7% in the fourth decade of life.54 In
older individuals, the tumour tends to arise in more
unusual locations such as the flat bones or the skull.
Males are affected more frequently than females at
a ratio of 2 : 1.
Radiographically, chondroblastoma presents as an
epiphyseal or apophyseal, oval, lytic mass with scattered
punctate areas of mineralization (Fig. 15).56 The tumour

Figure 15 Axial CT through distal femur containing a chondroblastoma. The tumour is oval, well circumscribed and lytic with
spotty calcifications.

GIANT CELL CONTAINING LESIONS OF BONE AND THEIR DIFFERENTIAL DIAGNOSIS

Figure 16 Chondroblastoma composed of sheets of chondroblasts with scattered osteoclast-like giant cells. Note the difference in morphology of the nuclei in the giant cells and the
chondroblasts.

Figure 17 Chondroblastoma with poorly formed cartilage

matrix that is focally mineralized producing a chicken wire-like
pattern.

is well circumscribed, frequently has sclerotic margins

and there is no or minimal periosteal reaction in most
cases. Larger tumours and those arising in the flat bones
can expand the contour of the bone.
Grossly, chondroblastoma is tan-grey, and occasionally yellow. It is solid, but cystic change is commonplace.
Histologically, the tumour is densely cellular and
composed of sheets of chondroblasts admixed with
scattered multinucleated osteoclast-type giant cells
(Fig. 16). The chondroblasts are polyhedral and have
a moderate amount of cytoplasm and centrally located
nuclei. The nuclei have characteristic longitudinal
grooves and clefts causing them to resemble the nuclei of
Langerhans histiocytes. The chondroblasts can be
mitotically active; however, the mitotic figures are of
normal structure. The multinucleated osteoclast-like
cells vary in number and may be few or innumerable.
Their nuclei are oval, vesicular and are not grooved;
therefore, their appearance differs from those of the

243

chondroblasts. The matrix in chondroblastoma consists

of poorly formed hyaline cartilage that is present in
small amounts (Fig. 17). It may appear basophilic or
eosinophilic and it is deposited in such a manner that it
surrounds individual cells forming inconspicuous lacunar
spaces. The matrix frequently mineralizes in a linear
pattern outlining individual chondroblasts which
produces the so-called chicken wire pattern of
mineralization that is characteristic of chondroblastoma
(Fig. 17). Secondary change in chondroblastoma includes
cystic degeneration that may have the appearance of an
aneurysmal bone cyst or simple cyst. The tumour can
also undergo coagulative necrosis and this is most
frequent in areas that are mineralized.
The chondroblasts have ultrastructural features
suggestive of poorly formed chondrocytes.57 Their round
or oval nuclei are deeply indented and have a thick
fibrillar lamina along the inner aspect of the nuclear
membrane. Rough endoplasmic reticulum and Golgi
are not prominent and the cytoplasm contains small
aggregates of glycogen, mitochondria and filaments.57
Immunohistochemically, chondroblastoma stains for
vimentin and S-100, and can also express keratin,
epithelial membrane antigen, and actin.58}60 This staining
pattern is helpful in distinguishing chondroblastoma from
most of the other giant cell rich lesions in that the others
are negative for S-100.
Cytogenetic studies have been rarely reported for
chondroblastoma. Although no specific chromosomal
abnormality has been identified, aberrations in chromosomes 5 and 8 have been described in several studies.61
Chondroblastoma is a benign neoplasm that is usually
treated by curettage. Approximately 10% of cases locally
recur.55 Chondroblastoma rarely metastasizes and when
this occurs it frequently follows a local recurrence. The
metastatic deposits are usually located in the lung,
although other sites including the soft tissues have been
reported.55,62 The histological features of the primary
tumour and the metastasis are generally unrevealing
as they usually have the morphology of conventional
chondroblastoma.

MALIGNANT NEOPLASMS
Giant cell rich osteosarcoma
Osteosarcoma is the most common primary malignancy
of bone and accounts for approximately 20% of primary
bone sarcomas exclusive of myeloma. It is defined by the
presence of mesenchymal cells that synthesize and
deposit bone matrix. Osteosarcomas are heterogeneous
in their morphology and biological behaviour. The classic
osteosarcoma is an aggressive high-grade intramedullary
tumour that arises in the metaphyseal region of a long
bone in an adolescent. The giant cell rich variant of

244

CURRENT DIAGNOSTIC PATHOLOGY

Figure 19 Giant cell rich osteosarcoma with enlarged, hyperchromatic tumour cells admixed with benign osteoclast-like giant
cells.

Figure 18 Plain film of high-grade osteosarcoma showing

a poorly defined destructive mixed lytic and blastic mass arising in
the metaphysis and extending into the soft tissues.

osteosarcoma has many of the same clinicopathological

features of classic osteosarcoma.63,64
Osteosarcoma has a bi-modal age distribution. The
first and largest peak occurs during the second decade
and accounts for 75% of cases and the second smaller
peak spans the fourth to sixth decades of life.10 Males are
affected more frequently than females at a ratio of almost
1.4 : 1. Osteosarcomas can affect any bone of the
body; however, they have a propensity to arise in
the metaphyseal region of long tubular bones and
approximately 50% of cases develop about the knee.10
Osteosarcoma typically manifests radiographically as
a metaphyseal mixed lytic and blastic destructive mass
that has poorly defined margins (Fig. 18). The tumour
frequently transgresses the cortex eliciting a periosteal
reaction and invades into the neighbouring soft tissues.
Grossly, osteosarcoma is usually centred in the
metaphysis, is large ('10 cm), tan-white, and haemorrhagic, with areas of necrosis. The tumour frequently
destroys the cortex and forms a soft tissue mass.
Osteosarcoma is classified histologically into various
subtypes; the most common being osteoblastic,
chondroblastic and fibroblastic. The giant cell rich variant
is defined as an osteosarcoma in which more than 50% of
the tumour is composed of numerous benign osteoclastlike giant cells admixed with malignant bone forming
cells. The giant cell rich variant is rare and in the Mayo
Clinic series of over 1600 cases of osteosarcoma,
accounted for only 0.3% of cases.10 In most cases of
giant cell rich osteosarcoma, the malignant cells
demonstrate significant cytological atypia including

marked pleomorphism, hyperchromasia and have a high

rate of mitotic activity including those which are
structurally abnormal (Fig. 19).65 However, in some cases
the malignant cells are deceptively banal in appearance
and overall the neoplasm can closely mimic a giant cell
tumour. In this circumstance, extensive sampling
searching for neoplastic bone and careful clinical
correlation are required to make the correct diagnosis.
In fact, any neoplasm with the appearance of a giant cell
tumour that arises in the metaphysis of an adolescent
should be viewed with suspicion.
Osteosarcoma is currently treated with pre-operative
chemotherapy and limb salvage resection. Analysis of the
amount of chemotherapy-induced tumour necrosis in
the resection specimen helps determine which agents
are administered in the postoperative phase of systemic
therapy. Long-term survival rates are now in the range
of 70%.
PRACTICE POINTS
E
E

The osteoclast-like giant cell defines the family of

giant cell rich lesions of bone
Giant cell rich lesions of bone include reactive
lesions and benign and malignant neoplasms. Most
giant cell rich lesions of bone are benign
Giant cell rich lesions of bone can be distinguished
from one another based on their clinical, radiological and pathological features
Immunohistochemistry can be helpful in the
differential diagnosis of giant cell rich lesions

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