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WHO Classification of Tumors of Soft Tissue and Bone

Article · January 2013

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 Tumours of bone: Introduction R.J. Grimer
P.C.W. Hogendoorn
D. Vanel

Epidemiology and etiology decade of life, while the second occurs in Table 14.01 Predispositions for bone tumours
Among the wide array of human neo- people aged > 60 years. The risk of de- 011ier disease (enchondromatosis) snd Maffucci
plasms, primary tumours of bone are rel- velopment of bone sarcomas during the syndrome
atively common; however, clinically sig- second decade of life is close to that of
nificant bone neoplasms are infrequent. Familial retinoblastoma syndrome
the > 60 years population, but in absolute
numbers more cases develop in the sec- Li-Fraumeni syndrome
Incidence ond decade. Rothmund-Thomson syndrome
The true incidence of benign bone tu- Multiple osteochondromas
mours is unknown, although older radio- Predisposing lesions
graphical studies have suggested that a Paget disease
Although the majority of primary bone ma-
substantial proportion of the population lignancies appear to arise de novo, it is in- Radiation
has an indolent lesion. In contrast, bone creasinglyapparent that some develop in Fibrous dysplasia
sarcomas are rare and account for only association with recognizable precursors Bone infarction
0.2% of all neoplasms for which data were (Table 14.01). Paget disease, radiation in-
obtained in one large series {2020}. Com- Chronic osteomyelitis
jury, bone infarction, chronic osteomyelitis
parison of the incidence rate of bone sar- Metallic and polyethylene implants
and certain pre-existing benign tumours
comas with that of the closely related are the most clearly established precan- Osteogenesis imperfecta
group of soft tissue sarcomas indicates cerous conditions {23,502,986,1077,1259, Giant cell tumour of bone
that osseous neoplasms occur at a rate 2953,157,916,941,1908,2771}. Recently,
approximately one tenth that of their soft- attention has been focused on a small
tissue counterparts. The overall annual in- number of reported cases of bone sar- ation with retinoblastoma, Li-Fraumeni,
cidence rate for bone sarcomas in North coma arising in association with implanted and Rothmund-Thomson syndromes,
America and Europe is 0.8 per 100000 metallic hardware, joint prostheses and , t among others (Table 27.01). The most fre-
population. Somewhat higher incidence bone grafts, but a causal association has quent familial form of osteosarcoma oc-
rates were reported in Argentina and not been proven (978,1090,1392,2213, curs inthe autosomal dominant retinoblas-
Brazil (1.5-2) and Israel (1.4) {2190}. 1270,1392}. toma syndrome {746,1701,463, 1653,
The incidence rates of specific bone sarco- 2025,1102}. Affected family members
mss are age-related and as a group, have Genetic predisposition carry a germline alteration inactivating
a bimodal distribution. The first well-de- Osteosarcoma, the most frequent primary one of the R81 gene alleles. The role of
fined peak occurs during the second malignancy of bone, can develop in associ- the TP53 gene in the development of os-
teosarcoma is exemplified by its associa-
tion with the Li-Fraumeni syndrome char-
1.0 acterized by TP53 germline mutations
ó 0.9 - Osteosarcoma {1606,1607,1713,1008}. An increased risk
for the development of osteosarcoma has
ó 0.8 — Chondrosarcoma also been identified in families with Roth-
~ 0.7 mund-Thom son syndrome; RECQL4 mu-
° -- ~ Ewing sarcoma
Q 0.6 tations have been identified in approxi-
°' 0.5 — Chordoma mately two thirds of Rothmund-Thomson
— UPS syndrome patients {1430,2896,2897).
~ 0.4 _/
c 0.3 Clinical features
a~
:°
U
0.2 Bone tumours present in a number of dif-
~ 0.1 ferent ways:
• Pain
• Swelling
• Pathological fracture
• Loss of use/neurological changes
Age at diagnosis (years) • Incidental finding.
The most common presentation of a
Fig. 14.01 Age-specific incidence rates by histological subtype, all races, both sexes {1973}. UPS, undifferentiated
symptomatic benign tumour is an aching
pleomorphic sacoma.
pain that is frequently intermittent, but

244 Tumours of bone

many present for the first time witha patho- • Metastases
logical fracture in a previously asympto- • Malignant bone tumour
matic individual (e.g. a fractured humerus • Benign bone tumour BENIGN TUMOURS
through a simple bone cyst). Osteoid osteo- • Infection EPIPRPSIS
Chondroblesloma
mas typically present with night pain in the • Haematological disorder. Giant cell tumour
middle of a long bone that is relieved by Obtaining a diagnosis for a symptomatic
simple analgesics or anti-inflammatories. patient as quickly as possible is essential Osteoblastoma
Osteochondromas typically present as a but delays in diagnosis are frequent Os[eochoodroma
Non-ossifying 5órama
painless lump, whilst chondroblastomas {2585}. A simple algorithm based on the Osteoid osteoma
typically present with pain and stiffness of most likely diagnosis for a patient of a Chandromyxoid Hbrome
Giant cell tumo ur
the affected joint. particular age has been advocated
Clinical findings with bone tumours are (1038}. This is based on the fact that un- Enchoodrome
often very non specific. Swelling and ten- derthe age of 35 years, metastatic carci- Fibrous dysplasie

derness over the affected bone are the noma is uncommon, whilst over that age
most common findings, but there will be the likelihood of a bone tumour being a
limitation of joint movements if there is ei- metastasis from a known or undiagnosed MALIGNANT TIIMOIIRS
ther irritation of the joint by the tumour or carcinoma increases (1712). DIAPHYSlS
frank growth of tumour into the joint. Sys- Up to 43% of malignant bone tumours will Ewing sarcoma
Chondrosercoma
temicfindings are rare in primary bone tu- arise around the knee, but under the age
mours unless there is disseminated dis- of 20 years this rises to 56% (Table 14.02). hfETi1PHPS7S
Osteosercome
ease, or an associated condition such as Any child or adolescent therefore, with Juxtacortical osteosarcoros
multiple osteochondromas, 011ier disease pain and/or swelling around the knee that
or neurofibromatosis 1458}. does not settle, should have the possibil-
Malignant tumours typically present with ity of a bone tumour included in the diag- Fig.14.02 Common spatial distribution in the long bones
pain that gradually gets worse and is non- nosis and be investigated. of benign and malignant primary bone tumours.
mechanical in nature {2957]. By the time The second most common site is the
of diagnosis, many patients will be suffer- pelvis—which is numerically the most
ing with night pain that will be waking common site of presentation for both Ew- symptoms of pain or discomfort in the limb
them from sleep. As most bone tumours ing sarcoma and chondrosarcoma. De- and often minimal force causes the frac-
start inside the bone, swelling only be- lays in diagnosis here are frequent with ture. Awareness of the possibility of a
comes apparent once the cortex is symptoms being very non-specific and pathological cause for the fracture is es-
breached and the tumour starts to expand often long-lasting {2998}. Referred pain sential to prevent inadvertent internal fix-
either under or through the periosteum. to the leg or knee is not infrequent and ation {11}. Usually the history combined with
Swelling is thus a later presentation of many patients will have been investigated the imaging manifestations are sufficient.
bone tumours. The presence of swelling in prior to diagnosis without the possibility of Blood tests are not usually helpful in di-
a limb associated with pain, particularly a bone tumour being considered. Night agnosing bone tumours, with certain ex-
night pain, should always lead to further pain again is often the key that should ceptions. The alkaline phosphatase level
investigation. There is clearly a wide dif- alert the clinician to the possibility of a is raised in around 46% of patients with
ferential diagnosis for patients presenting bone tumour being present. osteosarcoma (and is a poor prognostic
in this manner with the most common di- Pathological fractures in bone tumours sign) (132}, whilst LDH, ESR and CRP may
agnoses being: are often associated with pre-existing be raised in Ewing sarcoma and again this
is a poor prognostic indicator {130},
Table 14.02 Most common locations of presentation for primary malignant bone tumours and overall risk of a
pathological fracture at time of diagnosis* Imaging
Diagnosis
Knee' Hip and Shoulder Lower Upper Trunk° Risk of
leg (%) limb (%) (%) pathological
A radiographical differential remains the
(%) pelvis° (%) girdle° (%)
fracture (°/a) first step in imaging of bone tumours. In
case of diagnostic problems, the next step
Osfeosarcoma 66 15 10 5 3 1 9
is CT. MRI is the main imaging modality for
Chondrosarcoma 17 48 15 4 9 7 12 local staging, treatment evaluation and de-
Ewing sarcoma 22 44 11 13 7 3 6 tection of recurrences. PET is still under
Undifferentiated 41 29 9 5 14 2 16 evaluation. Important parameters in imag-
pleomorphic sarcoma ing evaluation include tumour location,
All diagnoses 31 7 5 3 10
size, margins, type of matrix, and pe-
43 11
riosteal reaction. Certain tumours are more
'Data from 3000 primary malignant bone tumours seen at Royal Orthopaedic Hospital, Birmingham. common in particular bones. Adamantin-
a Knee tumours include distal femur, proximal tibia and proximal fibula, oma, usually found in adults, selectively in-
" Hip and pelvis tumours include pelvis and proximal femur locations. volvesthe anterior cortex of the shaft of the
` Shoulder girdle tumours include proximal humerus, scapula and clavicle.
° Trunk includes spine, ribs etc.
tibia. The most common epiphyseal tu-
mour in childhood is chondroblastoma,

Introduction 245
 and after the closure of the epiphyseal riosteal reaction, broken by the growth of Effectivene
plate, giant cell tumour is the most com- ss and follow-up of treatmep~
the tumour. It can be seen in both benign Some prima
mon. Tumour size may provide some in- ry malignant tumours arp
and malignant processes. Cortical disrup- treated with
sight as to the anticipated behaviour of preoperative chemotherapy
tion and soft-tissue involvement usually in- before remov
the lesion. A tumour < 6 cm in greatest di- al. MRI provides an accu.
dicate aggressiveness. Athin layer of new rate study
mension is likely to be benign whereas of the tumour volume. Signal
bone formation, ossified around the tu- decrease
one >ócm may be benign or malignant. on T2-weighted sequences in-
mour, suggests a slow evolution and there- dicates increa
The axis of the lesion is also useful to de- sed ossification or more
for abenign process, even if the cortex is fibrous
termine. Tumours are rarely centrally lo- tissue in the tumour {1204}. Lack
destroyed. On the contrary, tumour on increase signa oí
cated, such as simple bone cyst. They are in l intensity of the lesion af-
both sides of a not yet destroyed cortex in- ter inject
most often excentric. A cortical location is ion of the contrast agent sug.
dicates avery aggressive lesion {328}. Bests necrosis. MRI with dynamic
necessary to diagnose anon-ossifying Multiple lesions are seen in chondromas, enhancem contrast
fibroma. Finally, the tumour can be a sur- ent may be useful for differentiat-
osteochondromas, Langerhans cell histio- ing post-c
face lesion e.g. parosteal osteosarcoma. hemotherapeutic change from
cytosis, metastases, vascular tumours, viable tumou
The next step is to determine the limits of r (593,2837, 2877], but re-
and more rarely in multifocal osteosarco- sults are only reliable immediately
the tumour. The patterns of bone destruc- mas and metastatic Ewing sarcoma. before
tion indicate the aggressiveness of the surgery, and not after a single cycle
On the basis of clinical and radiological chemother of
lesion. Most lesions appear radiolucent apy, which would detect
signs, one should first diagnose benign changes
on the radiographs, but some are scle- attributable to treatment {1203).
lesions for which a subsequent biopsy
rotic. Arciform calcifications suggest car- may not be necessary: > metaphyseal Grading
tilaginous tumours. The pattern of peri- and staging
fibrous defect > fibrous dysplasia > os- Grading
osteal new bone formation reacting to the teochondroma > enchondroma > simple Bone tumou
tumour crossing the cortex depends upon rs vary widely in their biologi-
bone cyst > vertebral haemangioma. Ra- cal behav
the progression of the tumour. When the tu- iour. Histological grading is an
diography is always the starting point. CT attempt to
mour grows slowly, the periosteum has predict the behaviour of a mal-
provides additional information and is the ignant tumou
enough time to build a thick layer of bone. r based on histological fea-
examination of choice when the tumour is tures. There
When multiple layers of periosteal forma- is no generally accepted
arising in flat bones or axial skeleton. It is grading
tion are present, there is probably a suc- system for bone sarcomas and
the best technique to guide diagnostic the FNCLCC
cession of fast and slow growth phases of grading system used in soft
needle biopsies and perform radiofre- tissue sarco
progression. Perpendicular periosteal for- mas has never been validated
quency ablations {2342,2343}. Small lu- in bone tumou
mations are a very useful radiological sign, rs. In bone sarcomas, the
cency of the cortex, localized involvement histologica
strongly suggesting malignancy. The Cod- l subtype often determines
of the soft tissues, and thin peripheral pe- grade. For
man triangle indicates an elevated pe- 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
Table 14.03. Grading of bone sarcoma {2385} high grade, and parosteal
nign lesions and thick (> 1.5-2 cm in osteosarco
Gradé
ma is considered low grade.
Sarcoma type adults) in peripheral chondrosarcomas In conve
ntional chondrosarcoma, the
Grade I Parosteal osteosarcoma {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)
Grade I chondrosarcoma is widely used. Comparable to the
filled cavities, especially aneurysmal bone system propo
Clear cell chondrosarcoma sed in the Third Edition of the
cysts, more accurately than CT {2784). It WHO Class
ification of tumours of soft tis-
Low-grade intramedullary osteosarcoma can also help diagnose the low signal of fi- sue and bone,
a grouping into:
Grade II Periosteal osteosarcoma brous tissue, the high, lobulated signal of • Benig
n
cartilage on T2-weighted sequences and • Locall
Grade II chondrosarcoma y aggressive or rarely metastasizing
the inflammatory reaction around some • Malig
Classic adamantinoma . nant
bénign (osteoid osteoma, osteoblas- is propo
Chordoma
sed. Definitions of these cate-
toma, chondroblastoma) and vascular gories
are as follows along the lines of
Grade III Osteosarcoma (conventional, tumours {331}. MRI diffusion, perfusion the soft-tissu
e tumour counterparts:
telangiecta6c, small cell, secondary, high- and spectroscopy have limited diagnos-
grade surface) tic value {3060}. Benign
Undifferentiated high-grade pleomorphic Most benign bone tumours have a limited
sarcoma Radiographical staging capacity for local recurrence. Those that
Ewing sarcoma Focal extent and staging is based on MRI do recur
do so in anon-destructive fash-
{ 770]. Bone metastases are best detected ion
Grade III chondrosarcoma and are almost always readily cured
on radionuclide bone scans or whole by comp
Dedifferentiated chondrosarcoma lete local excision/curretage.
body MRI. Pulmonary metastases are
Mesenchymal chondrosarcoma evaluated on chest CT. Its sensitivity is Interm
ediate (locally aggressive)
Dedifferentiated chordoma quite good, but specificity remains poor Bone tumou
rs in this category often recur
Malignancy in giant cell tumour of bone { 2241 ]. locally and are associated with an infiltra-
tive and locally destructive growth pat-
246 Tumours of bone
 tern. Lesions in this category do not have (e.g. chondrosarcoma, periostal osteo- nificance of histological grading is limited
any evident potential to metastasize but sarcoma). It is important to note, that in by interobserver variability and the
typically require wide excision witha mar- fact
this new grouping, the intermediate cate- that the majority of tumours fall into the
in-
gin of normal tissue, or application of a lo- gories do not correspond to histologically termediate range. This resulted
in a two-
cal adjuvant in order to ensure local con- determined intermediate grade in a bone tier system simply designating a
tumour
trol. The prototypical lesion in this cate- sarcoma (see below), nor do they corre- as low grade (low and intermediate grade
gory is grade I chondrosarcoma. 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,
Intermediate (rarely metastasizing) The locally aggressive subset with no low-grade lesions have a <25% risk
of
Bone tumours in this category are often lo- metastatic potential, as defined above, metastasis. High-grade lesions have
cally aggressive (see above) but, in addi- a
are generally given ICD-O /1 codes, while great risk of local recurrence and > 25%
tion, show the well-documented ability to the rarely metastasizing lesions are given risk of distant spread. Guidelines for
give rise to distant metastases in occa- re-
ICD-O /3 codes. This categorization is es- porting and grading of bone tumours
sional cases. The risk of such metastases are
pecially useful for categorizing rarely available both from USA as well
as Euro-
appears to be < 2% and is not reliably metastasizing tumours, which in essence pean perspectives (2385,119
predictable on the basis of histomorphol- 7,1724A,
are considered benign, such as giant cell 1270}.
ogy. Metastasis in such lesions is usually tumour of bone, and sarcomas, which in
to the lung. Prototypical examples in this practice do not metastasize like atypical Staging
category include giant cell tumour of cartilaginous tumour/chondrosarcoma In bone tumours, TNM staging
bone. includes
grade I. When osteosarcoma, leiomyosar- histological subtype, size, continuity,
coma and so-called fibrosarcoma of bone grade, as well as the local and
Malignant distant
need to be graded, cellularity, i.e. the rel- spread, in order to estimate the prognosis
In addition to the potential for locally de- ative proportion of cells to matrix, and nu- of the patient. Lymph-node metastase
structive growth and recurrence, malig- s in
clear features of the tumour cells are the bone sarcomas are rare. The special stag-
nant bone tumours (known as bone sar- most important criteria used for grading. ing system adopted by the musculo-
comas) have a significant risk of distant Generally, the higher the grade, the more skeletal society first described by Ennek-
metastasis, ranging in most instances cellular the tumour. Irregularity of the nu- ing and co-authors has gained accept-
from 20% to almost 100%, depending clear contours, enlargement and hyper- ance {2985}. Although staging systems
upon histological type and grade. Sóme chromasia ofthe nuclei are correlated with have been described for both benign
(but not all) histologically low-grade sar and
grade. Mitotic figures and necrosis are malignant bone tumours, the usefulness
comas have a metastatic risk of only 2- is
additional features useful in grading {788}. primarily in the description of malignant
10%, but such lesions may advance in While a number of grading systems are bone tumours {62,2196}.
grade in a local recurrence, and thereby used worldwide, athree-tier grading sys-
acquire a higher risk of distant spread 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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