ORTHOPAEDIC ONCOLOGY
Basic science of
musculoskeletal tumours
Kenneth S Rankin
Abstract
The basic science of musculoskeletal tumours is a complex subject
and has been historically related to pathological descriptions of the le-
sions. Our understanding of these conditions has increased rapidly
with the advent of genetic sequencing and molecular diagnostic tech-
niques. This article covers the main topics and touches on the relevant
research strategies which seek to open up further management op-
tions, particularly for the sarcomas.
Keywords basic science; musculoskeletal tumours; sarcoma
Introduction
Musculoskeletal tumours encompass a wide variety of entities,
and our understanding of them has been historically based on the
traditional pathological descriptions of the lesions. These de-
scriptions have evolved into a classification system, of which the
World Health Organization (WHO) classification of bone and soft
tissue tumours is the essential cornerstone.1 The histological
features of the tumours are now complemented by an array of
cytogenetic and molecular diagnostic assays which are increas-
ingly useful for those cases which are equivocal and for further
confirmation of a diagnosis. An example of this is cytogenetics to
confirm presence of the EWS/FLI1 fusion product in a suspected
Ewings sarcoma with a histological description of small round
blue cells along with immunohistochemical staining that dem-
onstrates high expression of CD99. Another example would be an
equivocal case of an active lytic bone lesion that is likely to be
benign but with persistent concern that it may actually be a
telangiectatic osteosarcoma. The presence of a USP6 rearrange-
ment on cytogenetic testing in such a case would be reassuring
that it is an aneurysmal bone cyst, which of course has major
implications on the treatment strategy. Therefore it is the pro-
gressive understanding of the basic science of these lesions
which allows us to improve upon diagnosis and management of
this diverse group of musculoskeletal tumours. This section will
cover the important basic science features of musculoskeletal
tumours including tissue of origin, whether the lesion is benign
or malignant, common features and pathophysiology. There
will also be a discussion of research strategies in the basic sci-
ence arena which serves to improve our understanding of these
conditions and ultimately leads to advances in diagnosis and
management.
Kenneth S Rankin MBChB MD FRCS Honorary Consultant in
Orthopaedic Oncology, Northern Institute for Cancer Research,
Newcastle University, UK; North of England Bone and Soft Tissue
Tumour Service, Freeman Hospital, Newcastle upon Tyne, UK.
Conicts of interest: none declared.
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Tissues of origin
Musculoskeletal tumours can arise from several main tissue
sources. The majority of primary lesions originate from mesen-
chymal tissue which is analogous to the mesoderm in embryo-
logical terms. Neuroectodermal tissue can give rise to primary
nerve sheath tumours in the musculoskeletal system and some
primary lesions develop from primitive neuroectodermal tissue
which is a remnant of embryological neuron precursors. Tu-
mours may be secondary due to spread from carcinomas, with
bone being the most common site. These metastatic lesions are
therefore of epithelial origin, but have a complex interaction with
their host site. Haematological conditions can manifest as
musculoskeletal tumours, the main ones encountered by the
orthopaedic surgeon being myeloma and lymphoma. Finally,
syndromic conditions may give rise to widespread musculo-
skeletal tumours which are often benign but need to be closely
observed for malignant transformation.
Tumours of mesenchymal origin
There is a vast array of primary benign and malignant tumours
which arise in the musculoskeletal system. Benign tumours
consist of dozens of subtypes based upon histological descrip-
tion. Malignant tumours are mainly the sarcomas of which more
than 50 types are described and again, histological description is
the mainstay of classification.1 Broadly, benign tumours are
defined by their inability to metastasize but can be locally
aggressive and therefore pose significant management problems,
as exemplified by fibromatosis. Malignant tumours have the
potential to metastasize and cause death and therefore manage-
ment is complex and multi-modal to optimize outcomes. There
are some intermediate tumours which are often locally aggres-
sive but very rarely metastasize such as giant cell tumour of
bone. It is important to consider that some benign tumours have
the potential to undergo malignant transformation, such as the
large atypical lipomas.
Benign versus malignant tumours
The large number of musculoskeletal tumours is too extensive to
list but they can be placed into groups to make initial manage-
ment decisions easier. Figures 1 and 2 show flow diagrams for
benign and malignant tissue tumours respectively.
The diagnosis of benign lesions may be achieved with clinical
examination and imaging only, but if there is doubt a biopsy,
usually in the clinic may be required for confirmation. Manage-
ment is then dependent on whether the patient is symptomatic or
if the lesion has a risk of malignant transformation then excision
may be advised.
The largest group of patients with malignant lesions in the
musculoskeletal system consists of those suffering from meta-
static carcinoma or myeloma affecting bone. Many of these pa-
tients require surgical intervention to prevent an impending
pathological fracture or to treat a fracture that has already
occurred. It is important to remember that melanoma can
metastasize to bone and therefore if there is doubt about the
origin of a lesion a biopsy should be performed. The manage-
ment of bone and soft tissue sarcomas (STS) and metastatic
disease has been dealt with in chapters 4 and 5.
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 ORTHOPAEDIC ONCOLOGY

Intermediate bone tumours which rarely metastasize

C Giant cell tumour of bone
C Chordoma
C Epithelioid haemangioma
C Epithelioid haemangioendothelioma
C Adamantinoma

Table 1

of their lesions, particularly if it increases in size or becomes

painful.
Enchondromas are commonly referred for further evaluation
Figure 1 A basic ow chart of benign orthopaedic oncology lesions. when they are noted incidentally on an MRI scan for joint pain,
typically in the distal femur. It is important to re-scan these le-
sions to assess for change and in some centres dynamic contrast
Finally, there are some locally aggressive bone lesions with a
MRI is used to distinguish between enchondroma and grade 1
low risk of metastasizing. These are listed in Table 1. These le-
chondrosarcoma.2
sions should be managed by a bone sarcoma centre.
Benign soft tissue tumours
Benign bone tumours
There are a huge range of benign soft tissue lesions encountered
These lesions will be seen by orthopaedic surgeons in a diverse
by the orthopaedic surgeon. Lipomas and ganglia are the most
range of subspecialties and can often be dealt with minimal input
common. Diagnosis should be confirmed by ultrasound and
from an orthopaedic oncology centre. If there is any concern
management is based on symptoms. Deep lipomas (subfascial/
regarding the diagnosis, it is important that the lesion is dis-
intramuscular) may reach impressive sizes. MRI is required to
cussed with the local oncology team and investigations with the
exclude areas of dedifferentiation prior to marginal excision.
appropriate imaging and biopsy performed. Some benign lesions
Many of these large deep lipomas will be given a diagnosis of
may require excision by an orthopaedic oncologist if the
atypical lipomatous tumour (ALT) by the pathologist based on
anatomical location would require an extensive approach with
cellular atypia and positive p16 (tumour suppressor protein),
mobilization of neurovascular structures (Figure 3). A detailed
MDM2 (tumour promotor protein) and CDK4 (cell cycle regu-
review of benign bone tumours is provided in the article on
lator) immunostaining.3 Loss of p16 activity and MDM2 ampli-
Management of benign bone tumours in this issue (http://dx.doi.
fication are postulated to be potential events that may lead to the
org/10.1016/j.mporth.2017.03.008).
transformation of ALT into liposarcoma.4
It is also important to consider that a benign bone lesion may
be related to a syndrome, for example multiple hereditary exos-
tosis (EXT gene mutations) or multiple enchondromatosis, the
underlying pathophysiology of which is unclear. Such patients
need to be monitored closely for malignant transformation in one

Figure 3 A large sessile osteochondroma arising from the posterior

aspect of the proximal tibia. An MRI to check the size of the cartilage
cap and position of the critical structures is important pre-operatively.
Figure 2 Flow chart depicting the main three groups of orthopaedic A formal posterior approach to the knee is required with mobilization of
oncology malignant lesions. the neurovasular bundle to safely excise the lesion.

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10.1016/j.mporth.2017.03.009
 ORTHOPAEDIC ONCOLOGY
Malignant primary bone sarcomas
The three main bone sarcomas are osteosarcoma, Ewings sar-
coma and chondrosarcoma. Each of these malignancies display
unique biological characteristics which impact on medical and
surgical management.
Osteosarcoma
The origin of the osteosarcoma cells is likely to be an osteoblast
precursor which undergoes an oncological event during rapid
cell division, classically at the physis which is the anatomical site
of most lesions. The genetic map of osteosarcoma is complex and
despite concerted efforts to identify clear targetable mutations
via next generation sequencing, there has been little progress.
Mutations and deletions of the TP53 gene which encodes for
the p53 tumour suppression protein have been described but
this is not directly targetable. Research efforts therefore continue
to try and discover novel targets and there are clinical trials
running involving a tyrosine kinase inhibitor (lenvatinib) for
relapsed osteosarcoma and an immune check point antibody
pembrolizumab.
Ewings sarcoma
This malignancy most often occurs in bone, however there are
some soft tissue variants. About 85% are driven by the EWS/
FLI1 fusion product with the other 15% featuring different
translocations. Ewings sarcoma is usually very chemosensitive
and is also radiosensitive. This may be due to the lack of an
extracellular matrix which provides a barrier to therapy in many
solid tumours. Further details on the commonest translocation
are described in the histology and diagnostic section below.
Chondrosarcoma
This cartilage producing bone tumour is resistant to chemo-
therapy and generally to radiotherapy unless situated in the skull
base. The glycosaminoglycan rich chondroid matrix expressed by
the tumour cells may be a factor in mediating resistance to
therapy. Surgery is therefore the mainstay of treatment but local
recurrence can become a difficult problem with the grade of the
sarcoma increasing over time. Potential new therapeutic targets
include isocitrate dehydrogenase (IDH) mutations as identified
by next generation sequencing5 and immunotherapy against
neuron glial antigen-2 which is a heavy transmembrane proteo-
glycan highly expressed on the surface of chondrosarcoma cells.6
Malignant primary STS
STS are a diverse range of malignancies which can arise in any
site with connective tissue. Most are managed with surgery and
radiotherapy. Chemotherapy tends to play a minor role in most
cases although can be very effective in certain paediatric types
such as rhabdomyosarcoma. The commonest type of STS
encountered is the myxofibrosarcoma which is diagnosed on
descriptive grounds on the histology. Myxofibrosarcomas display
interesting infiltrative behaviour which is the subject of emerging
research studies as the pathophysiology is poorly understood. In
contrast, synovial sarcoma which is driven by a particular fusion
product has been studied in depth with recent findings revealing
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that the SS18/SSX fusion product causes oncogenesis via the
perturbation of BAF complexes which regulate DNA folding.7
These findings are important as there may be therapies that
can be developed to improve the medical management of syno-
vial sarcomas which are often resistant to chemotherapy.
Neuroectodermal
The orthopaedic oncologist will deal with musculoskeletal tu-
mours arising from neuroectodermal tissue on a regular basis
because these lesions occur in peripheral nerves. There are
benign and malignant forms and there are genetic conditions
which lead to multiple lesions. The commonest nerve sheath
tumour encountered is the schwannoma. These are benign and
most are easily excised. Recently a schwannomatosis disorder
has been described which shares some clinical features with
neurofibromatosis type 2, but is now recognized to be a distinct
condition with a particular driver mutation.8 Neurofibromatosis
type 1 is a condition where patients suffer from a range of neu-
rofibromas many of which may be excised during their lifetime.
In patients with neurofibromatosis and schwannomatosis, clini-
cians must be alert to the possibility of malignant transformation
in a lesion. The precise biology leading to malignant change in a
lesion involves the dysregulation of tumour suppressor pathways
caused by the underlying genetic mutations.
Metastatic and haematological tumours
Malignant bone lesions in the form of metastases from primary
carcinoma along with the haematological malignancies myeloma
and lymphoma are commonly encountered in orthopaedic prac-
tice. Carcinoma cells that metastasize into bone will interact with
their host environment and in certain types, lytic lesions are the
result which leads to an impending or actual pathological frac-
ture, classically in the proximal femur. The development of these
lytic lesions is not from direct bone resorption by the cancer cells,
it is via the stimulation of osteoclast formation (Figure 4).
Similar mechanisms are involved in the development of lytic
lesions in myeloma with the added effect of osteoblast inhibition
by the tumour cells which accounts for the widespread skeletal
destruction in this condition and the accompanying cold bone
scan in most cases. Prostate carcinoma bone lesions are usually
osteosclerotic. This is due to stimulation of osteoblast activity by
prostate carcinoma cells via the expression of endothelin-1.
Common histological descriptions and accompanying
diagnostics
It is important to consider that histological descriptions originate
from the microscopic appearances of the tumour cells and their
surrounding extracellular matrix. As well as some vivid terms
which accurately capture the appearance of the lesion, there are
some misnomers. The commonest example of a misnomer is
synovial sarcoma which suggests that this is a malignant tumour
arising in a synovial joint. This is not the case e most of these
lesions arise in connective tissue outside of a joint, however the
microscopic appearance of the cells is similar to synoviocytes
which gave rise to the term. Common histological descriptions
which are often utilized to test knowledge of the subject in ex-
aminations include:
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 ORTHOPAEDIC ONCOLOGY

Figure 4 Carcinoma cells establish in bone via invasion of the unmineralized bone matrix and then may stimulate osteoclast resorption via the
RANKL pathway which leads to the classic lytic lesions commonly seen in orthopaedic practice. TGFb transforming growth factor beta; IGF
insulin-like growth factor; PDGF platelet derived growth factor; BMPs bone morphogenic proteins; MMP-1 matrix metalloproteinase-1;
RANKL receptor activator of nuclear kappa ligand.

lace-like osteoid between malignant spindle cells
(osteosarcoma)

malignant cells in a chondroid or myxoid matrix
(chondrosarcoma)

physaliferous (leaf-like) cells (chordoma)

chicken wire calcification (chondroblastoma)

alphabet soup (fibrous dysplasia).
With the development of cytogenetic and molecular di-
agnostics, the pathology report of many lesions will include
relevant details regarding associated translocations, gene ampli-
fications and the expression of particular cellular proteins as
assessed using immunohistochemistry. Figure 5 illustrates the
typical EWS/FLI1 translocation found in 85% of Ewings sar-
coma cases. This fusion gene results in the production of an
abnormal protein which is the oncodriver in Ewings sarcoma.
Translocations are detected using fluorescent in situ hybridi-
zation (FISH) or reverse transcriptase polymerase chain reaction
(RT-PCR). Table 2 lists some of the known translocations

Figure 5 (a) The translocation of the EWS gene from locus 24 on the q arm of chromosome 11 to locus 12 (in which the FLI1 gene resides) onto the
q arm of chromosome 22 results in the nomenclature t(11;22)(q24;q12). (b) The fusion gene EWS/FLI1 encodes an abnormal protein which is the
oncodriver in the cells leading to the promotion of rapid cell division, invasion and metastasis.

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 ORTHOPAEDIC ONCOLOGY

stain is for membrane type-1 matrix metalloproteinase (MT1-

Commonly encountered translocations in MMP) which cleaves collagen in the extracellular matrix.
musculoskeletal tumours and their resultant fusion
products Research strategies
Tumour type Translocation Fusion product There are key strategies that have been developed to try and
improve the coherence of research in musculoskeletal tumours.
Aneurysmal bone cyst t(16;17)(q22;p13) CDH11/USP6
In the United Kingdom, there are functional groups in the Na-
Ewings sarcoma t(11;22)(q24;q12) EWS/FLI1a
tional Cancer Research Institute (NCRI) which bring together
Synovial sarcoma t(x;18)(p11.2;q11.2) SS18/SSXb
clinicians and scientists to co-ordinate projects and foster
Myxoid liposarcoma t(12;16)(q13;p11) CHOP/TLS
collaboration. This mainly focusses on the sarcomas and consists
Extraskeletal myxoid t(9;22)(q22;q12) EWSR1/CHN
of the Sarcoma Clinical Studies Group which itself contains bone
chondrosarcoma
tumour and young onset STS subgroups. Extensive genetic
Clear cell sarcoma t(12;22)(q13;q12) EWSR1/ATF1
sequencing of osteosarcoma and chondrosarcoma has been
a
About 85% of Ewings sarcoma, the other 15% are driven by other fusion performed under the auspices of the International Cancer
products. Genome Consortium and has been successful in identifying IDH
b
Also known as SYT/SSX.
mutations in chondrosarcoma which may lead to novel therapy.
Table 2
Summary
The basic science of musculoskeletal tumours encompasses a
vast range of entities. While a lot of the biology has been
described, there is still a huge amount to learn about these
conditions and the focus is on developing more effective thera-
pies mainly for the sarcomas that are still devastating in terms of
morbidity and mortality. A

Figure 6 Poorly differentiated soft tissue sarcoma with immunohisto-
chemical staining for membrane type-1 matrix metalloproteinase
(MT1-MMP). The intense brown staining (white arrows) is due to high
expression of MT1-MMP on the sarcoma cell membrane. This enzyme
cleaves collagen to facilitate invasion of the extra cellular matrix. The
blue colour is haematoxylin which stains the cell nuclei. The broblast
cells in the fascia are negative for MT1-MMP.
encountered in musculoskeletal tumours. Aneurysmal bone cysts
are non-malignant but the fusion product does drive the locally
aggressive behaviour of these tumours.
Sarcoma invasion
Many sarcomas express matrix metalloproteinases which direct
tumour cell invasion and metastasis and further understanding of
the mechanisms of action of these enzymes may open up thera-
peutic avenues. Figure 6 illustrates the invasive front of a poorly
differentiated rapidly enlarging STS. The immunohistochemical
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