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WHO Classification of Tumors of Soft Tissue and Bone

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 Tumours of bone: Introduction
Epidemiology and etiology
Among the wide array of human neo-
plasms, primary tumours of bone are rel-
atively common; however, clinically sig-
nificant bone neoplasms are infrequent.
Incidence
The true incidence of benign bone tu-
mours is unknown, although older radio-
graphical studies have suggested that a
substantial proportion of the population
has an indolent lesion. In contrast, bone
sarcomas are rare and account for only
0.2% of all neoplasms for which data were
obtained in one large series {2020}. Com-
parison of the incidence rate of bone sar-
comas with that of the closely related
group of soft tissue sarcomas indicates
that osseous neoplasms occur at a rate
approximately one tenth that of their soft-
tissue counterparts. The overall annual in-
cidence rate for bone sarcomas in North
America and Europe is 0.8 per 100000
population. Somewhat higher incidence
rates were reported in Argentina and
Brazil (1.5-2) and Israel (1.4) {2190}.
The incidence rates of specific bone sarco-
mss are age-related and as a group, have
a bimodal distribution. The first well-de-
fined peak occurs during the second
1.0
ó 0.9
ó 0.8
~ 0.7
Q 0.6
°' 0.5
~ 0.4
c 0.3
a~
:°
U
0.2
~ 0.1
Fig. 14.01 Age-specific incidence rates by histological subtype, all races, both sexes {1973}. UPS, undifferentiated
pleomorphic sacoma.
244 Tumours of bone
decade of life, while the second occurs in
people aged > 60 years. The risk of de-
velopment of bone sarcomas during the
second decade of life is close to that of
the > 60 years population, but in absolute
numbers more cases develop in the sec-
ond decade.
Predisposing lesions
Although the majority of primary bone ma-
lignancies appear to arise de novo, it is in-
creasinglyapparent that some develop in
association with recognizable precursors
(Table 14.01). Paget disease, radiation in-
jury, bone infarction, chronic osteomyelitis
and certain pre-existing benign tumours
are the most clearly established precan-
cerous conditions {23,502,986,1077,1259,
2953,157,916,941,1908,2771}. Recently,
attention has been focused on a small
number of reported cases of bone sar-
coma arising in association with implanted
metallic hardware, joint prostheses and ,
bone grafts, but a causal association has
not been proven (978,1090,1392,2213,
1270,1392}.
Genetic predisposition
Osteosarcoma, the most frequent primary
malignancy of bone, can develop in associ-
- Osteosarcoma
— Chondrosarcoma
° -- ~ Ewing sarcoma
— Chordoma
— UPS
_/
Age at diagnosis (years)
R.J. Grimer
P.C.W. Hogendoorn
D. Vanel
Table 14.01 Predispositions for bone tumours
011ier disease (enchondromatosis) snd Maffucci
syndrome
Familial retinoblastoma syndrome
Li-Fraumeni syndrome
Rothmund-Thomson syndrome
Multiple osteochondromas
Paget disease
Radiation
Fibrous dysplasia
Bone infarction
Chronic osteomyelitis
Metallic and polyethylene implants
Osteogenesis imperfecta
Giant cell tumour of bone
ation with retinoblastoma, Li-Fraumeni,
and Rothmund-Thomson syndromes,
t among others (Table 27.01). The most fre-
quent familial form of osteosarcoma oc-
curs inthe autosomal dominant retinoblas-
toma syndrome {746,1701,463, 1653,
2025,1102}. Affected family members
carry a germline alteration inactivating
one of the R81 gene alleles. The role of
the TP53 gene in the development of os-
teosarcoma is exemplified by its associa-
tion with the Li-Fraumeni syndrome char-
acterized by TP53 germline mutations
{1606,1607,1713,1008}. An increased risk
for the development of osteosarcoma has
also been identified in families with Roth-
mund-Thom son syndrome; RECQL4 mu-
tations have been identified in approxi-
mately two thirds of Rothmund-Thomson
syndrome patients {1430,2896,2897).
Clinical features
Bone tumours present in a number of dif-
ferent ways:
• Pain
• Swelling
• Pathological fracture
• Loss of use/neurological changes
• Incidental finding.
The most common presentation of a
symptomatic benign tumour is an aching
pain that is frequently intermittent, but
many present for the first time witha patho-
logical fracture in a previously asympto-
matic individual (e.g. a fractured humerus
through a simple bone cyst). Osteoid osteo-
mas typically present with night pain in the
middle of a long bone that is relieved by
simple analgesics or anti-inflammatories.
Osteochondromas typically present as a
painless lump, whilst chondroblastomas
typically present with pain and stiffness of
the affected joint.
Clinical findings with bone tumours are
often very non specific. Swelling and ten-
derness over the affected bone are the
most common findings, but there will be
limitation of joint movements if there is ei-
ther irritation of the joint by the tumour or
frank growth of tumour into the joint. Sys-
temicfindings are rare in primary bone tu-
mours unless there is disseminated dis-
ease, or an associated condition such as
multiple osteochondromas, 011ier disease
or neurofibromatosis 1458}.
Malignant tumours typically present with
pain that gradually gets worse and is non-
mechanical in nature {2957]. By the time
of diagnosis, many patients will be suffer-
ing with night pain that will be waking
them from sleep. As most bone tumours
start inside the bone, swelling only be-
comes apparent once the cortex is
breached and the tumour starts to expand
either under or through the periosteum.
Swelling is thus a later presentation of
bone tumours. The presence of swelling in
a limb associated with pain, particularly
night pain, should always lead to further
investigation. There is clearly a wide dif-
ferential diagnosis for patients presenting
in this manner with the most common di-
agnoses being:
Table 14.02 Most common locations of presentation for primary malignant bone tumours and overall risk of a
pathological fracture at time of diagnosis*
Knee' Hip and
(%) pelvis° (%)
Osfeosarcoma 66 15
Chondrosarcoma 17 48
Ewing sarcoma 22 44
Undifferentiated 41 29
pleomorphic sarcoma
All diagnoses 31
43
'Data from 3000 primary malignant bone tumours seen at Royal Orthopaedic Hospital, Birmingham.
a Knee tumours include distal femur, proximal tibia and proximal fibula,
" Hip and pelvis tumours include pelvis and proximal femur locations.
` Shoulder girdle tumours include proximal humerus, scapula and clavicle.
° Trunk includes spine, ribs etc.
• Metastases
• Malignant bone tumour
• Benign bone tumour
• Infection
• Haematological disorder.
Obtaining a diagnosis for a symptomatic
patient as quickly as possible is essential
but delays in diagnosis are frequent
{2585}. A simple algorithm based on the
most likely diagnosis for a patient of a
particular age has been advocated
(1038}. This is based on the fact that un-
derthe age of 35 years, metastatic carci-
noma is uncommon, whilst over that age
the likelihood of a bone tumour being a
metastasis from a known or undiagnosed
carcinoma increases (1712).
Up to 43% of malignant bone tumours will
arise around the knee, but under the age
of 20 years this rises to 56% (Table 14.02).
Any child or adolescent therefore, with
pain and/or swelling around the knee that
does not settle, should have the possibil-
ity of a bone tumour included in the diag-
nosis and be investigated.
The second most common site is the
pelvis—which is numerically the most
common site of presentation for both Ew-
ing sarcoma and chondrosarcoma. De-
lays in diagnosis here are frequent with
symptoms being very non-specific and
often long-lasting {2998}. Referred pain
to the leg or knee is not infrequent and
many patients will have been investigated
prior to diagnosis without the possibility of
a bone tumour being considered. Night
pain again is often the key that should
alert the clinician to the possibility of a
bone tumour being present.
Pathological fractures in bone tumours
are often associated with pre-existing
Shoulder Lower Upper Trunk° Risk of
leg (%) limb (%) (%) pathological
girdle° (%)
fracture (°/a)
10 5 3 1 9
15 4 9 7 12
11 13 7 3
9 5 14 2 16
7 5 3 10
11
BENIGN TUMOURS
EPIPRPSIS
Chondroblesloma
Giant cell tumour
Osteoblastoma
Os[eochoodroma
Non-ossifying 5órama
Osteoid osteoma
Chandromyxoid Hbrome
Giant cell tumo ur
Enchoodrome
Fibrous dysplasie
MALIGNANT TIIMOIIRS
DIAPHYSlS
Ewing sarcoma
Chondrosercoma
hfETi1PHPS7S
Osteosercome
Juxtacortical osteosarcoros
Fig.14.02 Common spatial distribution in the long bones
of benign and malignant primary bone tumours.
symptoms of pain or discomfort in the limb
and often minimal force causes the frac-
ture. Awareness of the possibility of a
pathological cause for the fracture is es-
sential to prevent inadvertent internal fix-
ation {11}. Usually the history combined with
the imaging manifestations are sufficient.
Blood tests are not usually helpful in di-
agnosing bone tumours, with certain ex-
ceptions. The alkaline phosphatase level
is raised in around 46% of patients with
osteosarcoma (and is a poor prognostic
sign) (132}, whilst LDH, ESR and CRP may
be raised in Ewing sarcoma and again this
is a poor prognostic indicator {130},
Imaging
Diagnosis
A radiographical differential remains the
first step in imaging of bone tumours. In
case of diagnostic problems, the next step
is CT. MRI is the main imaging modality for
local staging, treatment evaluation and de-
6 tection of recurrences. PET is still under
evaluation. Important parameters in imag-
ing evaluation include tumour location,
size, margins, type of matrix, and pe-
riosteal reaction. Certain tumours are more
common in particular bones. Adamantin-
oma, usually found in adults, selectively in-
volvesthe anterior cortex of the shaft of the
tibia. The most common epiphyseal tu-
mour in childhood is chondroblastoma,
Introduction 245
 and after the closure of the epiphyseal
plate, giant cell tumour is the most com-
mon. Tumour size may provide some in-
sight as to the anticipated behaviour of
the lesion. A tumour < 6 cm in greatest di-
mension is likely to be benign whereas
one >ócm may be benign or malignant.
The axis of the lesion is also useful to de-
termine. Tumours are rarely centrally lo-
cated, such as simple bone cyst. They are
most often excentric. A cortical location is
necessary to diagnose anon-ossifying
fibroma. Finally, the tumour can be a sur-
face lesion e.g. parosteal osteosarcoma.
The next step is to determine the limits of
the tumour. The patterns of bone destruc-
tion indicate the aggressiveness of the
lesion. Most lesions appear radiolucent
on the radiographs, but some are scle-
rotic. Arciform calcifications suggest car-
tilaginous tumours. The pattern of peri-
osteal new bone formation reacting to the
tumour crossing the cortex depends upon
the progression of the tumour. When the tu-
mour grows slowly, the periosteum has
enough time to build a thick layer of bone.
When multiple layers of periosteal forma-
tion are present, there is probably a suc-
cession of fast and slow growth phases of
progression. Perpendicular periosteal for-
mations are a very useful radiological sign,
strongly suggesting malignancy. The Cod-
man triangle indicates an elevated pe-
Table 14.03. Grading of bone sarcoma {2385}
Gradé
Sarcoma type
Grade I Parosteal osteosarcoma
Grade I chondrosarcoma
Clear cell chondrosarcoma
Low-grade intramedullary osteosarcoma
Grade II Periosteal osteosarcoma
Grade II chondrosarcoma
Classic adamantinoma .
Chordoma
Grade III Osteosarcoma (conventional,
telangiecta6c, small cell, secondary, high-
grade surface)
Undifferentiated high-grade pleomorphic
sarcoma
Ewing sarcoma
Grade III chondrosarcoma
Dedifferentiated chondrosarcoma
Mesenchymal chondrosarcoma
Dedifferentiated chordoma
Malignancy in giant cell tumour of bone
246 Tumours of bone
riosteal reaction, broken by the growth of Effectivene
ss and follow-up of treatmep~
the tumour. It can be seen in both benign Some prima
ry malignant tumours arp
and malignant processes. Cortical disrup- treated with
preoperative chemotherapy
tion and soft-tissue involvement usually in- before remov
al. MRI provides an accu.
dicate aggressiveness. Athin layer of new rate study
of the tumour volume. Signal
bone formation, ossified around the tu- decrease
on T2-weighted sequences in-
mour, suggests a slow evolution and there- dicates increa
sed ossification or more
for abenign process, even if the cortex is fibrous
tissue in the tumour {1204}. Lack
destroyed. On the contrary, tumour on increase signa oí
in l intensity of the lesion af-
both sides of a not yet destroyed cortex in- ter inject
ion of the contrast agent sug.
dicates avery aggressive lesion {328}. Bests necrosis. MRI with dynamic
Multiple lesions are seen in chondromas, enhancem contrast
ent may be useful for differentiat-
osteochondromas, Langerhans cell histio- ing post-c
hemotherapeutic change from
cytosis, metastases, vascular tumours, viable tumou
r (593,2837, 2877], but re-
and more rarely in multifocal osteosarco- sults are only reliable immediately
mas and metastatic Ewing sarcoma. before
surgery, and not after a single cycle
On the basis of clinical and radiological chemother of
apy, which would detect
signs, one should first diagnose benign changes
attributable to treatment {1203).
lesions for which a subsequent biopsy
may not be necessary: > metaphyseal Grading
and staging
fibrous defect > fibrous dysplasia > os- Grading
teochondroma > enchondroma > simple Bone tumou
rs vary widely in their biologi-
bone cyst > vertebral haemangioma. Ra- cal behav
iour. Histological grading is an
diography is always the starting point. CT attempt to
predict the behaviour of a mal-
provides additional information and is the ignant tumou
r based on histological fea-
examination of choice when the tumour is tures. There
is no generally accepted
arising in flat bones or axial skeleton. It is grading
system for bone sarcomas and
the best technique to guide diagnostic the FNCLCC
grading system used in soft
needle biopsies and perform radiofre- tissue sarco
mas has never been validated
quency ablations {2342,2343}. Small lu- in bone tumou
rs. In bone sarcomas, the
cency of the cortex, localized involvement histologica
l subtype often determines
of the soft tissues, and thin peripheral pe- grade. For
instance, Ewing sarcoma, mes-
riosteal reaction can be seen. CT also allows enchymal
chondrosarcoma and dediffer-
measurement of the cartilage cap thickness entiated
chondrosarcoma are always
in osteochondroma: the cuff is thin in be- considered
high grade, and parosteal
nign lesions and thick (> 1.5-2 cm in osteosarco
ma is considered low grade.
adults) in peripheral chondrosarcomas In conve
ntional chondrosarcoma, the
{1400}. MRI is rarely useful in the diagno- gradi
ng system as proposed by Evans et
sis, but can display fluid levels in blood- al {788)
is widely used. Comparable to the
filled cavities, especially aneurysmal bone system propo
sed in the Third Edition of the
cysts, more accurately than CT {2784). It WHO Class
ification of tumours of soft tis-
can also help diagnose the low signal of fi- sue and bone,
a grouping into:
brous tissue, the high, lobulated signal of • Benig
n
cartilage on T2-weighted sequences and • Locall
y aggressive or rarely metastasizing
the inflammatory reaction around some • Malig
nant
bénign (osteoid osteoma, osteoblas- is propo
sed. Definitions of these cate-
toma, chondroblastoma) and vascular gories
are as follows along the lines of
tumours {331}. MRI diffusion, perfusion the soft-tissu
e tumour counterparts:
and spectroscopy have limited diagnos-
tic value {3060}. Benign
Most benign bone tumours have a limited
Radiographical staging capacity for local recurrence. Those that
Focal extent and staging is based on MRI do recur
do so in anon-destructive fash-
{ 770]. Bone metastases are best detected ion
and are almost always readily cured
on radionuclide bone scans or whole by comp
lete local excision/curretage.
body MRI. Pulmonary metastases are
evaluated on chest CT. Its sensitivity is Interm
ediate (locally aggressive)
quite good, but specificity remains poor Bone tumou
rs in this category often recur
{ 2241 ]. locally and are associated with an infiltra-
tive and locally destructive growth pat-
 tern. Lesions in this category do not have
any evident potential to metastasize but
typically require wide excision witha mar-
gin of normal tissue, or application of a lo-
cal adjuvant in order to ensure local con-
trol. The prototypical lesion in this cate-
gory is grade I chondrosarcoma.
Intermediate (rarely metastasizing)
Bone tumours in this category are often lo-
cally aggressive (see above) but, in addi-
tion, show the well-documented ability to
give rise to distant metastases in occa-
sional cases. The risk of such metastases
appears to be < 2% and is not reliably
predictable on the basis of histomorphol-
ogy. Metastasis in such lesions is usually
to the lung. Prototypical examples in this
category include giant cell tumour of
bone.
Malignant
In addition to the potential for locally de-
structive growth and recurrence, malig-
nant bone tumours (known as bone sar-
comas) have a significant risk of distant
metastasis, ranging in most instances
from 20% to almost 100%, depending
upon histological type and grade. Sóme
(but not all) histologically low-grade sar
comas have a metastatic risk of only 2-
10%, but such lesions may advance in
grade in a local recurrence, and thereby
acquire a higher risk of distant spread
(e.g. chondrosarcoma, periostal osteo- nificance of histological grading is limited
sarcoma). It is important to note, that in by interobserver variability and the
fact
this new grouping, the intermediate cate- that the majority of tumours fall into the
in-
gories do not correspond to histologically termediate range. This resulted
in a two-
determined intermediate grade in a bone tier system simply designating a
tumour
sarcoma (see below), nor do they corre- as low grade (low and intermediate grade
spond to the ICD-O /1 category described in three-tier system) or high grade (grade
as uncertain whether benign or malignant. 3 and 4 in four-tier system). In
general,
The locally aggressive subset with no low-grade lesions have a <25% risk
of
metastatic potential, as defined above, metastasis. High-grade lesions have
a
are generally given ICD-O /1 codes, while great risk of local recurrence and > 25%
the rarely metastasizing lesions are given risk of distant spread. Guidelines for
re-
ICD-O /3 codes. This categorization is es- porting and grading of bone tumours
are
pecially useful for categorizing rarely available both from USA as well
as Euro-
metastasizing tumours, which in essence pean perspectives (2385,119
7,1724A,
are considered benign, such as giant cell 1270}.
tumour of bone, and sarcomas, which in
practice do not metastasize like atypical Staging
cartilaginous tumour/chondrosarcoma In bone tumours, TNM staging
includes
grade I. When osteosarcoma, leiomyosar- histological subtype, size, continuity,
coma and so-called fibrosarcoma of bone grade, as well as the local and
distant
need to be graded, cellularity, i.e. the rel- spread, in order to estimate the prognosis
ative proportion of cells to matrix, and nu- of the patient. Lymph-node metastase
s in
clear features of the tumour cells are the bone sarcomas are rare. The special stag-
most important criteria used for grading. ing system adopted by the musculo-
Generally, the higher the grade, the more skeletal society first described by Ennek-
cellular the tumour. Irregularity of the nu- ing and co-authors has gained accept-
clear contours, enlargement and hyper- ance {2985}. Although staging systems
chromasia ofthe nuclei are correlated with have been described for both benign
and
grade. Mitotic figures and necrosis are malignant bone tumours, the usefulness
is
additional features useful in grading {788}. primarily in the description of malignant
While a number of grading systems are bone tumours {62,2196}.
used worldwide, athree-tier grading sys-
tem seems to be most widely used. The sig-
Introduction 247
World Health Organization Classification of Tumours
~,~ oÍ~ ~~
lV,~ ~l
WHO V ~ ~ OMS
~
J~I~~i

International Agency for Research on Cancer (IARC)

4th Edition

WHO Classification of Tumours of

Soft Tissue and Bone

Edited by

Christopher D.M. Fletcher

Julia A. Bridge
Pancras C.W. Hogendoorn
Fredrik Mertens

International Agency for Research on Cancer

Lyon, 2013

WALREUS BIBLIQTH~EEK
Le9ds Universitair Metlisch Centrum, C1-Q
Rotbus 5600 - 2340 RC Lefden
Tel. 071- ~2~ 38 9~0

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