dd of giant cell lesions

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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 theirdifferential 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 tomake 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. Thekey 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 hyperparathy-

roidism. 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

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 locationsinclude 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 radiographicdifferential 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 admix-

ture 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


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Table 1 Giant cell lesions of bone

Reactive Benign Malignant

Brown tumour Giant cell reparative granuloma Osteosarcoma

Haemophiliac pseudotumour Non-ossifying fibroma Malignant fibrous histiocytoma

Intraosseous haemorrhage Giant cell tumour Clear cell chondrosarcoma

Aneurysmal bone cyst (ABC) Metastatic carcinoma

Chondroblastoma

Chondromyxoid fibroma

Langerhans cell histiocytosis

Pigmented villonodular synovitis

Figure 1 Axial CT of brown tumour in a rib. The tumour iswell demarcated, expands the bone, and has a lobular configura-

tion.

Figure 2 Brown tumour compartmentalized by septae con-

taining reactive bone.

Figure 3 Brown tumour composed of fibroblasts, osteoclast-

like giant cells and extravasated red blood cells.

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 cellreparative 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.

236 CURRENT DIAGNOSTIC PATHOLOGY


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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.

Figure 5 Giant cell tumour composed of syncytium of mono-

nuclear cells admixed with many osteoclast-like giant cells.

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 notuntil 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 notclear 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

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 areusually 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 isa 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 well-

delineated 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 wherethey 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

GIANT CELL CONTAINING LESIONS OF BONE AND THEIR DIFFERENTIAL DIAGNOSIS 237


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Figure 6 Tissue from periphery of giant cell tumour com-

posed 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 notdiagnostic 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 mononuclearcells 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.

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 mostrecurrences 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 occurde 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 inTable 1.

Its most important distinguishing histological feature isthe 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 giantcell 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 withpatients 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



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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.

Figure 8 Giant cell reparative granuloma composed of fas-

cicles of fibroblasts with osteoclast-like giant cells clustering

around a focus of haemorrhage.

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 characte-

ristically 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 tothe 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 andfeet, 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-

tionally, scattered lymphocytes, haemosiderin depositsand 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 hyperpara-

thyroidism 2also represents a giant-cell reparative

granuloma.19 Every patient with GCRG should therefore

have the appropriate tests to rule out hyperparathy-

roidism. 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. Anothertumour 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



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Figure 9 Plain film of non-ossifying fibroma showing an eccen-

tric, lytic mass with sclerotic margins in the metaphysis of the distal

tibia.

Figure 10 Non-ossifying fibroma characterized by cellular fas-

cicles of spindle cells arranged in a storiform pattern with scat-

tered osteoclast-like giant cells.

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 ap-

plied 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 spontaneousresolution 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 formsa 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

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.



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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 12 Axial MRI of aneurysmal bone cyst showing charac-

teristic fluid}fluid levels.

Figure 13 Aneurysmal bone cyst with numerous cyst spaces

filled with blood.

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 histo-logical 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.

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 ofvertebral 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.

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 osteoclast-

type giant cells, and reactive woven bone(Fig. 14). The

reactive woven bone is lined by osteoblasts and its



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Figure 14 Cyst wall of aneurysmal bone cyst composed of

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

Figure 15 Axial CT through distal femur containing a chon-

droblastoma. The tumour is oval, well circumscribed and lytic with

spotty calcifications.

deposition follows the contours of the fibrous septa.

Approximately, one-third of cases contain a cartilage-likematrix, 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 inassociation 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 considereda 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-

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

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



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Figure 16 Chondroblastoma composed of sheets of chon-

droblasts with scattered osteoclast-like giant cells. Note the differ-

ence 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 occasion-

ally yellow. It is solid, but cystic change is commonplace.

Histologically, the tumour is densely cellular andcomposed 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

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 whichproduces 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 Golgiare 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 chromo-

somes 5 and 8 have been described in several studies.61

Chondroblastoma is a benign neoplasm that is usuallytreated 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



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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.

Figure 19 Giant cell rich osteosarcoma with enlarged, hyper-

chromatic tumour cells admixed with benign osteoclast-like giant

cells.

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 almost1.4 : 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 haemor-

rhagic, with areas of necrosis. The tumour frequentlydestroys 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 osteoclast-

like 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 theamount 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

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. Mostgiant cell rich lesions of bone are benign

Giant cell rich lesions of bone can be distinguished

from one another based on their clinical, radio-

logical and pathological features

Immunohistochemistry can be helpful in the

differential diagnosis of giant cell rich lesions

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