bb5_16.qxd 13.9.2006 11:19 Page 225
WHO Classification
of Bone Tumours
Primary neoplasms of the skeleton are rare, amounting to
only 0.2% of the overall human tumour burden. However,
children are frequently affected and the aetiology is
largely unknown.
Significant progress has been made in the histological
and genetic typing of bone tumours. Furthermore,
advances in combined surgical and chemotherapy
havelead to a significant increase in survival rates even
for highly malignant neoplasms, including osteosarcoma
and Ewing sarcoma.
Several bone tumours occur in the setting of inherited
tumour syndromes, but their histology differs little from
the respective sporadic counterparts.
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WHO classification of bone tumours
CARTILAGE TUMOURS GIANT CELL TUMOUR
Osteochondroma 9210/0* Giant cell tumour 9250/1
Chondroma 9220/0 Malignancy in giant cell tumour 9250/3
Enchondroma 9220/0
Periosteal chondroma 9221/0
Multiple chondromatosis 9220/1 NOTOCHORDAL TUMOURS
Chondroblastoma 9230/0 Chordoma 9370/3
Chondromyxoid fibroma 9241/0
Chondrosarcoma 9220/3
Central, primary, and secondary 9220/3 VASCULAR TUMOURS
Peripheral 9221/3 Haemangioma 9120/0
Dedifferentiated 9243/3 Angiosarcoma 9120/3
Mesenchymal 9240/3
Clear cell 9242/3
SMOOTH MUSCLE TUMOURS
Leiomyoma 8890/0
OSTEOGENIC TUMOURS Leiomyosarcoma 8890/3
Osteoid osteoma 9191/0
Osteoblastoma 9200/0
Osteosarcoma 9180/3 LIPOGENIC TUMOURS
Conventional 9180/3 Lipoma 8850/0
chondroblastic 9181/3 Liposarcoma 8850/3
fibroblastic 9182/3
osteoblastic 9180/3
Telangiectatic 9183/3 NEURAL TUMOURS
Small cell 9185/3 Neurilemmoma 9560/0
Low grade central 9187/3
Secondary 9180/3
Parosteal 9192/3 MISCELLANEOUS TUMOURS
Periosteal 9193/3 Adamantinoma 9261/3
High grade surface 9194/3 Metastatic malignancy
FIBROGENIC TUMOURS MISCELLANEOUS LESIONS
Desmoplastic fibroma 8823/0 Aneurysmal bone cyst
Fibrosarcoma 8810/3 Simple cyst
Fibrous dysplasia
Osteofibrous dysplasia
FIBROHISTIOCYTIC TUMOURS Langerhans cell histiocytosis 9751/1
Benign fibrous histiocytoma 8830/0 Erdheim-Chester disease
Malignant fibrous histiocytoma 8830/3 Chest wall hamartoma
EWING SARCOMA/PRIMITIVE JOINT LESIONS
NEUROECTODERMAL TUMOUR Synovial chondromatosis 9220/0
Ewing sarcoma 9260/3
___________________________________________________________
Morphology code of the International Classification of Diseases
*
for Oncology (ICD-O) {726} and the Systematized Nomenclature
HAEMATOPOIETIC TUMOURS
of Medicine (http://snomed.org). Behaviour is coded /0 for benign tumours,
Plasma cell myeloma 9732/3
/1 for unspecified, borderline or uncertain behaviour, /2 for in situ carcino-
Malignant lymphoma, NOS 9590/3 mas and grade III intraepithelial neoplasia, and /3 for malignant tumours.
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H.D. Dorfman D. Vanel
WHO classification of tumours of
B. Czerniak Y.K. Park
R. Kotz K.K. Unni
bone: Introduction
Among the wide array of human neo- malignant fibrous histiocytoma, account- lar skeleton has a tendency to decrease
plasms, primary tumours of bone are rel- ing for a marked decline in the frequency with age. In patients older than fifty,
atively uncommon. Not only has this con- of the former diagnostic category. osteosarcoma of the extremity bones
tributed to the paucity of meaningful and makes up only 50 % of cases. In this
useful data about the relative frequency Age and site distribution group, the pelvis and craniofacial bones
and incidence rates of the various sub- The age-specific frequencies and inci- each account for about 20 % of the
types of bone tumours, but it also dence rates of bone sarcomas as a cases. The incidence rate of extremity
explains our rudimentary understanding group are clearly bimodal. The first well bone involvement for patients older than
of risk factors. defined peak occurs during the second 50 is approximately one third of that for
Little information is available concerning decade of life, while the second occurs persons in the younger age groups.
the aetiology and epidemiologic features in patients older than sixty. The risk of Chondrosarcomas have age-specific
of benign bone tumours since most pub- development of bone sarcomas during incidence rates showing a gradual
lished statistical studies have dealt with the second decade of life is close to that increase up to age 75. The age adjusted
bone sarcomas. The benign lesions will of the older than 60 population, but there rates show little difference by sex and
be considered from the epidemiologic are more cases in the second decade. race. More than 50 % of chondrosarco-
and aetiologic standpoint under the indi- The bimodal age-specific incidence rate mas occur in the long bones of the
vidual chapter headings, where they are pattern of bone sarcomas is clearly dif- extremities. The other major sites of
known. ferent from that of soft tissue sarcomas, involvement are the pelvis and ribs. The
which shows a gradual increase of inci- latter site and the sternum are high risk
Incidence dence with age. sites for malignant cartilage tumours.
In general, bone sarcomas account for Osteosarcoma occurs predominantly in Ewing sarcoma has epidemiological fea-
only 0.2% of all neoplasms for which patients younger than age twenty, and in tures similar to those of osteosarcoma,
data were obtained in one large series this group 80% occur in long bones of but while osteosarcomas tend to occur in
(SEER) {1789}. Comparison of the inci- the extremities. In this age group, a small the metaphyseal areas of long bones of
dence rate of bone sarcomas with that of proportion of cases involve other parts of skeletally immature patients, particularly
the closely related group of soft tissue the skeleton, such as craniofacial bones, in the knee region, Ewing sarcoma tends
sarcomas indicates that osseous neo- the spine, and pelvis. The clear predilec- to arise in the diaphysis. The age-specif-
plasms occur at a rate approximately tion of osteosarcoma for the appendicu- ic relative frequency and incidence mir-
one tenth that of their soft tissue counter-
parts {537,946,1304}.
In North America and Europe, the inci-
dence rate for bone sarcomas in males is
approximately 0.8 new cases per 100,000
population and year. Somewhat higher
incidence rates have been observed for
males in Argentina and Brazil (1.5-2) and
Israel (1.4) {1665}. Cancer registry data
with histological stratification indicate that
osteosarcoma is the most common pri-
mary malignant tumour of bone, account-
ing for approximately 35 percent of
cases, followed by chondrosarcoma
(25%), and Ewing sarcoma (16%). In
countries and regions with higher inci-
dence rates, the relative fraction of osteo-
sarcomas appears to be larger.
Chordomas and malignant fibrous histio-
cytoma are much less frequent, constitut-
ing approximately 8 and 5% of bone
tumours, respectively. In recent years, the
diagnosis of fibrosarcoma primary in
Fig. B.1 Age-specific incidence rates by histological subtype, all races, both sexes, SEER data, 1973-1987. MFH,
bone has largely been replaced by that of malignant fibrous histiocytoma and fibrosarcoma.
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Relative frequencies of bone sarcomas by histological type, sex, and race: SEER data 1973-1987
es of bone malignancies, other expo-
sures and conditions have been suspect-
Total White Black
ed (e.g. chromium, nickel, cobalt, alu-
Histological type No. % No. % No. %
minum, titanium, methyl-methacrylate,
and polyethyelene) but not unequivocally
Osteosarcoma 922 35.1 743 32.6 106 57.9
confirmed. Recently attention has been
focused on a small number of reported
Chondrosarcoma 677 25.8 615 27.0 35 19.1
cases of bone sarcomas arising in asso-
Ewing sarcoma 420 16.0 392 17.3 7 3.8
ciation with implanted metallic hardware
and joint prostheses {788, 879,
Chordoma 221 8.4 200 8.8 4 2.2
1083,1683,2225}. However, the epidemi-
ological evidence for a causitive role is
Malignant fibrous histiocytoma 149 5.7 125 5.5 13 7.1
still limited or inconclusive {6}. Future
Angiosarcoma 36 1.4 35 1.5 1 0.5 molecular epidemiological studies in
patients who have undergone ortho-
Unspecified 32 1.2 27 1.2 3 1.6
paedic implantation of metallic and other
foreign materials may provide clues to
Other 170 6.4 139 6.1 14 7.8
the pathogenetic mechanisms underlying
Total 2627 100.0 2276 100.0 183 100.0
malignant transformation in bone.
____________
From H. Dorfman & B. Czerniak {537}.
Clinical features
The clinical features of bone tumours are
non-specific, therefore a long period of
ror those of osteosarcoma with the major lesions that predispose to malignant time may elapse until the tumour is diag-
peak occurring during the second transformation. Others are benign neo- nosed. Pain, swelling and general discom-
decade of life. Although there is a rapid plasms that can be the source of a malig- fort are the cardinal symptoms that lead to
decrease in incidence after age 20, nant neoplastic process. The likelihood of the diagnosis of bone tumours. However,
cases are seen in all age groups. Unlike discovering such associated lesions can limited mobility and spontaneous fracture
osteosarcoma, Ewing sarcoma is report- be facilitated by attention to clinicopatho- may also be important features.
ed to occur almost exclusively in the logical correlation of all available data
white population. before arriving at a diagnosis. In bone,
the inclusion of radiographic imaging
Precursor lesions data in the diagnostic process offers a
Although the majority of primary bone unique opportunity to discover clues to
malignancies arise do novo, it is increas- causal relationships that may not be
ingly apparent that some develop in reflected in histological patterns or in
association with recognizable precursors. other laboratory data. This is especially
Some of these represent non-neoplastic true when serial radiographs are avail-
able for review.
Paget disease, radiation injury, and some
Precursors of malignancy in bone
of the more common benign cartilaginous
Fig. B.2 Osteochondroma. Hard, smooth, nodular
dysplasias are the most clearly estab-
High Risk
swelling of the distal femur, skin and soft tissues are
lished precancerous conditions. Both
Ollier disease (Enchondromatosis)
easily movable and the knee joint is freely mobile.
osteosarcoma and malignant fibrous his-
and Maffucci syndrome
tiocytoma have been linked to pre-exist-
Familial retinoblastoma syndrome
ing condition of bone such as Paget dis-
Rothmund-Thomson syndrome (RTS)
ease, radiation damage, bone infarction,
Moderate Risk
fibrous dysplasia, chronic osteomyelitis,
Multiple osteochondromas
and some genetically determined syn-
Polyostotic Paget disease
dromes {25,132,390,797,867,989,1042,
Radiation osteitis
2263}. The relative rarity of malignant
transformation in fibrous dysplasia,
Low Risk
osteomyelitis, bone cysts, osteogenesis
Fibrous dysplasia
imperfecta, and bone infarction places
Bone infarct
these conditions in a separate category
Chronic osteomyelitis
{540,725,760, 892,1471,2122}.
Metallic and polyethylene implants
Osteogenesis imperfecta
Fig. B.3 Osteosarcoma, causing swelling in the dis-
Giant cell tumour
Aetiology
tal femur. Soft tissues poorly movable, consistency
Osteoblastoma and chondroblastoma
While radiation and chronic inflammatory
ranging from tough to hard, hyperthermia of the skin
states are established, though rare caus- and marked veins.
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bb5_16.qxd 13.9.2006 11:19 Page 229
additional complaints. Swelling is only fibromas. In cases of malignant bone
observed if there is an extraosseous part of tumours, fracture is a rather rare primary
the tumour or the bone is expanded by the event, as it usually occurs in advanced
tumourous process. In malignant tumours, stages of osteolytic malignant tumours
swelling develops more rapidly. A descrip- and the patient will have experienced
tion of consistency is important e.g. hard, pain and tumour growth prior to it.
coarse, tightly elastic or soft. Metric data
concerning swelling (in centimeters) General symptoms
should be given; ultrasonic examination These mainly consist of fever, exhaustion
may be helpful to establish objective sizes. and loss of weight. They are late signs in
In advanced stages, tumour swelling may malignant tumours, and will be absent in
also cause skin changes, including tensed nearly all cases of benign bone lesions.
shining skin with prominent veins, livid
colouring, hyperthermia, as well as stria-
tion of the skin and eventually, ulceration. Imaging of bone tumours
The mobility of the skin, subcutis and mus- Diagnosis
culature above the tumour should also be Combining both radiological and histo-
assessed. The less the mobility, the more logical criteria is most appropriate.
likely is this factor a criterion of malignancy. Based on clinical and radiological signs,
one should first diagnose benign lesions
Limitation of movement for which a subsequent biopsy may not
Mobility may be limited in cases of be necessary:
Fig. B.4 Ewing sarcoma of the proximal humerus,
lesions close to the joint, in tumours such > Metaphyseal fibrous defect
presenting as tightly elastic, tense, ulcerated
lesion with shining skin, on a grey-white back- as osteoblastoma, chrondroblastoma, > Fibrous dysplasia
ground. Note the marked veins and skin striation.
giant cell tumours and all types of sarco- > Osteochondroma
mas. Occasionally it is not the tumour but > Enchondroma
reactive synovitis in the joint, especially > Simple bone cyst
Pain in chondroblastoma, that causes limita- > Vertebral haemangioma
Pain is the first and most common symp- tion of movement and masks the true Age is useful information: before age of
tom in nearly all malignant bone tumours diagnosis. 5, a malignant tumour is often metastatic
{388,429,1025,1159,1254}. If a sponta- neuroblastoma; between 5 and 15 years
neous fracture does not occur, the symp- Pathologic fracture old, osteosarcoma or Ewing sarcoma;
toms usually commence slowly. Initially Fracture is diagnosed early, as it causes and after 40 years, metastasis or myelo-
the patient has tearing neuralgia-like the patient to seek attention immediately. ma.
pain, which may also be interpreted as It may occur with no prior symptoms at The first step is to determine tumour
"rheumatic pain". Although the symptoms all, as is frequently the case in juvenile aggressiveness by conventional radiolo-
may initially occur intermittently and only cysts and in some non-ossifying bone gy. Important parameters include tumour
at rest, the pain might subsequently
become more intense, disturb sleep at
night, spread into the adjacent joint and
is frequently misinterpreted as arthritis or
as a post-traumatic phenomenon.
A further intensification of pain is experi-
enced as a persistent and piercing pain.
During disease progression, the pain
becomes excruciating and intolerable,
requiring opiate treatment.
In case of pressure on nerve trunks or
nerve plexuses, the patient may experi-
ence radiating pain. A specific kind of
pain occurs when the tumour is located
in the spine and causes radicular or
spinal compression symptoms with
paralysis.
Swelling
The second most important symptom in
bone tumours is swelling, which may fre-
quently be of very long duration, especial-
ly in benign neoplasms, and cause no Fig. B.5 The choice of the imaging technique.
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TNM Classification of bone tumours
destruction indicate the aggressiveness
of the lesion. Type 1 is the geographic
pattern. 1A is characterized by a rim of
Primary tumour (T) TX: primary tumour cannot be assessed
sclerosis between the normal and lytic
T0: no evidence of primary tumour
area. 1B indicates a very well limited
T1: tumour 8 cm in greatest dimension
lesion, with sharp separation with normal
T2: tumour > 8 cm in greatest dimension
bone, but no sclerosis. 1C characterizes
T3: discontinuous tumours in the primary bone site
a less sharp limit. Type 2 is the moth-
eaten pattern. It is made of multiple holes
separated by not yet destroyed bone
Regional lymph nodes (N) NX: regional lymph nodes cannot be assessed
and indicates a more aggressive growth.
N0: no regional lymph node metastasis
Type 3 is the permeative pattern.
N1: regional lymph node metastasis
Indistinct transition indicates a very rapid
progression of the lesion. The pattern of
Note: Regional node involvement is rare and cases in which nodal status is not assessed either
the margins of the tumour only means the
clinically or pathologically could be considered N0 instead of NX or pNX.
rate of progression of the lesion and not
directly its malignancy.
Most lesions appear radiolucent on the
Distant metastasis (M) MX: distant metastasis cannot be assessed
radiographs but some are sclerotic. The
M0: no distant metastasis
typical arciform calcifications suggest
M1: distant metastasis
cartilaginous tumours.
M1a: lung
The pattern of periosteal new bone for-
M1b: other distant sites
mation reacting to the tumour crossing
the cortex depends upon the rate of pro-
gression of the tumour. When the tumour
G Histopathological Grading
grows slowly, the periosteum has enough
Translation table for  three and  four grade to  two grade (low vs. high grade) system
time to build a thick layer of bone. When
multiple layers of periosteal formation are
TNM two grade system Three grade systems Four grade systems
present, there is probably a succession
of fast and slow growth phases of pro-
Low grade Grade 1 Grade 1
gression. Perpendicular periosteal for-
Grade 2
mations are a very useful radiological
High grade Grade 2 Grade 3
sign, strongly suggesting malignancy.
Grade 3 Grade 4
The Codman's triangle indicates an ele-
Note: Ewing sarcoma is classified as high grade.
vated periosteal reaction, broken by the
growth of the tumour. It can be seen in
both benign and malignant processes.
Stage IA T1 N0,NX M0 Low grade
Cortical disruption, and soft tissues
Stage IB T2 N0,NX M0 Low grade
involvement usually indicate aggressive-
Stage IIA T1 N0,NX M0 High grade
ness. A thin layer of new bone formation
Stage IIB T2 N0,NX M0 High grade
ossified around the tumour suggests a
Stage III T3 N0,NX M0 Any grade
slow evolution and therefore a benign
Stage IVA Any T N0,NX M1a Any grade
process, even if the cortex is destroyed.
Stage IVB Any T N1 Any M Any grade
On the contrary, tumour on both sides of
Any T Any N M1b Any grade
a not yet destroyed cortex indicates a
_______________________ very aggressive lesion.
From references {831,1979}. Multiple lesions are seen in chondromas,
osteochondromas, Langerhans cell histi-
ocytosis, metastases, and more rarely in
multifocal osteosarcomas and metastatic
location, size, type of matrix, and bigger than 6 cm may be benign or Ewing sarcoma.
periosteal reaction. Certain tumours are malignant. The axis of the lesion is also A flow chart of diagnostic procedures is
more common in particular bones. useful to determine. Tumours are rarely shown in Fig. B.05. In general, conven-
Adamantinoma, usually found in the centrally located, such as simple bone tional X-ray radiography is the starting
adult, selectively involves the tibia and cyst. They are most often eccentric. A point. CT is the examination of choice in
fibula. The most common epiphyseal cortical location is necessary to diag- the diagnosis of the nidus of osteoid
tumour in childhood is the chondroblas- nose a non-ossifying fibroma. Finally the osteoma in dense bone {798}. Small
toma. Tumour size is useful and easy to tumour can be a surface lesion. lucency of the cortex, localized involve-
use. A tumour less than 6 cm in greatest The next step is to determine the limits of ment of the soft tissues, and thin periph-
dimension is likely benign whereas one the tumour. The patterns of bone eral periosteal reaction can be seen
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Musculoskeletal Tumour Society staging of malignant bone lesions
al features useful in grading {624}.
Spindle cell sarcomas such as osteosar-
Stage: Definition:
coma and fibrosarcoma need to be grad-
ed. Many studies have shown that histo-
IA Low grade, intracompartmental
logical grading correlates with prognosis
in chondrosarcoma and malignant vas-
IB Low grade, extracompartmental
cular tumours {624,1006,1858}. Tumours
which are monomorphic, such as small
IIA High grade, intracompartmental
cell malignancies (Ewing sarcoma,
malignant lymphoma and myeloma), do
IIB High grade, extracompartmental
not lend themselves to histological grad-
ing. Mesenchymal chondrosarcomas
III Any grade, metastatic
and dedifferentiated chondrosarcomas
are always high grade, whereas clear
cell chondrosarcomas are low grade.
Clinicopathological studies have shown
Musculoskeletal Tumour Society staging. Surgical margins
that grading is not useful in predicting
Type: Plane of Dissection: prognosis in adamantinoma and chordo-
ma.
The significance of histological grading
Intralesional Within lesion
is limited by inter-observer variability and
the fact that the majority of tumours fall
Marginal Within reactive zone-extracapsular
into the intermediate range.
Wide Beyond reactive zone through normal tissue within compartment
Staging
In bone tumours, staging incorporates
Radical Normal tissue extracompartmental
the degree of differentiation as well as
local and distant spread, in order to esti-
mate the prognosis of the patient.
{279}. CT also allows measurement of the creased ossification or more fibrous tissue The universal TNM staging system used
thickness of a non-calcified cuff of a car- in the tumour {964}. Lack of increase in for most carcinomas is not commonly
tilaginous tumour: the cuff is thin in signal intensity of the lesion after injection used for sarcomas because of their rarity
benign lesions and thick (more than 3 of the contrast agent suggests necrosis. with which sarcomas metastasize to
cm) in chondrosarcomas {1092}. MRI is MR imaging with dynamic contrast- lymph nodes. Hence the special staging
rarely useful in the diagnosis, but can enhancement may be useful for differenti- system adopted by the musculoskeletal
display better than CT fluid levels in ating post-chemotherapeutic change society first described by Enneking and
blood filled cavities, especially aneurys- from viable tumour, because viable co-authors have gained acceptance
mal bone cysts. tumour enhances rapidly, and the post- {2291}. Although staging systems have
chemotherapeutic changes enhance been described for both benign and
Staging slowly {463,2175,2202}. malignant bone tumours, the usefulness
Focal extent and staging is based on is primarily in description of malignant
MRI {24,216,222}. The main advantages bone tumours. Benign lesions are classi-
are high contrast and the possibility of Grading and staging of bone sarcomas fied using Arabic numerals and malig-
choosing the plane of examination with- Grading nant ones with Roman numerals. Stage 1
out moving the patient. Histological grading is an attempt to pre- benign lesions are latent lesions having
Bone metastases are best detected on dict the biological behaviour of a malig- negligible recurrence rate following intra-
radionuclide bone scans. Pulmonary nant tumour based on histological fea- capsular excision. Stage 2 benign
metastases are evaluated on convention- tures. The principles used for grading lesions are actively growing with a signif-
al chest radiographs and chest CT sarcomas are similar to those proposed icant recurrence rate after intracapsular
{2185}. Positron emission tomography by Broders for grading of squamous cell procedures but a negligible recurrence
(PET) is still under evaluation. carcinoma {272}. In bone tumours, cellu- rate after marginal en bloc excision.
Effectiveness and follow-up of treatment larity, i.e., the relative amount of cells Stage 3 benign lesions are locally
Most primary malignant tumours are treat- compared to matrix, and nuclear features aggressive with extracapsular extension
ed with preoperative chemotherapy of the tumour cells are the most important having a high recurrence rate after either
before removal. Plain films and CT can criteria used for grading. Generally, the intracapsular or marginal procedures.
provide information on the size, margins higher the grade, the more cellular the A surgical staging system for malignant
and ossifications of the tumour. MRI, how- tumour. Irregularity of the nuclear con- lesions is most logically accomplished
ever, provides a more accurate study of tours, enlargement and hyperchromasia with the assessment of the surgical
the tumour volume. Signal decrease on of the nuclei are correlated with grade. grade (G), the local extent (T), and the
T2-weighted sequences suggests in- Mitotic figures and necrosis are addition- presence or absence of regional or dis-
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tant metastases (M). Any neoplasm can sis. High grade lesions (Broders grade 3 lesion is intracompartmental (A) or extra-
be divided into two grades; low (G1) and and grade 4) have a great risk of local compartmental (B) {55, 1677}. The pres-
high (G2). In general, low grade lesions recurrence and greater than 25% risk of ence or absence of metastasis (M) is the
correspond to Broders grade 1 and 2 distant spread. The anatomic extent (T) third major factor related to both progno-
and have less than 25% risk of metasta- is subdivided according to whether the sis and surgical planning.
232