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ORTHOPAEDICS AND TRAUMA --:- 1 Crown Copyright 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rankin KS, Basic science of musculoskeletal tumours, Orthopaedics and Trauma (2017), http://dx.doi.org/
10.1016/j.mporth.2017.03.009
ORTHOPAEDIC ONCOLOGY
Table 1
ORTHOPAEDICS AND TRAUMA --:- 2 Crown Copyright 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rankin KS, Basic science of musculoskeletal tumours, Orthopaedics and Trauma (2017), http://dx.doi.org/
10.1016/j.mporth.2017.03.009
ORTHOPAEDIC ONCOLOGY
Malignant primary bone sarcomas that the SS18/SSX fusion product causes oncogenesis via the
perturbation of BAF complexes which regulate DNA folding.7
The three main bone sarcomas are osteosarcoma, Ewings sar-
These findings are important as there may be therapies that
coma and chondrosarcoma. Each of these malignancies display
can be developed to improve the medical management of syno-
unique biological characteristics which impact on medical and
vial sarcomas which are often resistant to chemotherapy.
surgical management.
Neuroectodermal
Osteosarcoma
The orthopaedic oncologist will deal with musculoskeletal tu-
The origin of the osteosarcoma cells is likely to be an osteoblast
mours arising from neuroectodermal tissue on a regular basis
precursor which undergoes an oncological event during rapid
because these lesions occur in peripheral nerves. There are
cell division, classically at the physis which is the anatomical site
benign and malignant forms and there are genetic conditions
of most lesions. The genetic map of osteosarcoma is complex and
which lead to multiple lesions. The commonest nerve sheath
despite concerted efforts to identify clear targetable mutations
tumour encountered is the schwannoma. These are benign and
via next generation sequencing, there has been little progress.
most are easily excised. Recently a schwannomatosis disorder
Mutations and deletions of the TP53 gene which encodes for
has been described which shares some clinical features with
the p53 tumour suppression protein have been described but
neurofibromatosis type 2, but is now recognized to be a distinct
this is not directly targetable. Research efforts therefore continue
condition with a particular driver mutation.8 Neurofibromatosis
to try and discover novel targets and there are clinical trials
type 1 is a condition where patients suffer from a range of neu-
running involving a tyrosine kinase inhibitor (lenvatinib) for
rofibromas many of which may be excised during their lifetime.
relapsed osteosarcoma and an immune check point antibody
In patients with neurofibromatosis and schwannomatosis, clini-
pembrolizumab.
cians must be alert to the possibility of malignant transformation
in a lesion. The precise biology leading to malignant change in a
Ewings sarcoma
lesion involves the dysregulation of tumour suppressor pathways
This malignancy most often occurs in bone, however there are caused by the underlying genetic mutations.
some soft tissue variants. About 85% are driven by the EWS/
FLI1 fusion product with the other 15% featuring different Metastatic and haematological tumours
translocations. Ewings sarcoma is usually very chemosensitive
Malignant bone lesions in the form of metastases from primary
and is also radiosensitive. This may be due to the lack of an
carcinoma along with the haematological malignancies myeloma
extracellular matrix which provides a barrier to therapy in many
and lymphoma are commonly encountered in orthopaedic prac-
solid tumours. Further details on the commonest translocation
tice. Carcinoma cells that metastasize into bone will interact with
are described in the histology and diagnostic section below.
their host environment and in certain types, lytic lesions are the
result which leads to an impending or actual pathological frac-
Chondrosarcoma
ture, classically in the proximal femur. The development of these
This cartilage producing bone tumour is resistant to chemo- lytic lesions is not from direct bone resorption by the cancer cells,
therapy and generally to radiotherapy unless situated in the skull it is via the stimulation of osteoclast formation (Figure 4).
base. The glycosaminoglycan rich chondroid matrix expressed by Similar mechanisms are involved in the development of lytic
the tumour cells may be a factor in mediating resistance to lesions in myeloma with the added effect of osteoblast inhibition
therapy. Surgery is therefore the mainstay of treatment but local by the tumour cells which accounts for the widespread skeletal
recurrence can become a difficult problem with the grade of the destruction in this condition and the accompanying cold bone
sarcoma increasing over time. Potential new therapeutic targets scan in most cases. Prostate carcinoma bone lesions are usually
include isocitrate dehydrogenase (IDH) mutations as identified osteosclerotic. This is due to stimulation of osteoblast activity by
by next generation sequencing5 and immunotherapy against prostate carcinoma cells via the expression of endothelin-1.
neuron glial antigen-2 which is a heavy transmembrane proteo-
glycan highly expressed on the surface of chondrosarcoma cells.6 Common histological descriptions and accompanying
diagnostics
Malignant primary STS
It is important to consider that histological descriptions originate
STS are a diverse range of malignancies which can arise in any from the microscopic appearances of the tumour cells and their
site with connective tissue. Most are managed with surgery and surrounding extracellular matrix. As well as some vivid terms
radiotherapy. Chemotherapy tends to play a minor role in most which accurately capture the appearance of the lesion, there are
cases although can be very effective in certain paediatric types some misnomers. The commonest example of a misnomer is
such as rhabdomyosarcoma. The commonest type of STS synovial sarcoma which suggests that this is a malignant tumour
encountered is the myxofibrosarcoma which is diagnosed on arising in a synovial joint. This is not the case e most of these
descriptive grounds on the histology. Myxofibrosarcomas display lesions arise in connective tissue outside of a joint, however the
interesting infiltrative behaviour which is the subject of emerging microscopic appearance of the cells is similar to synoviocytes
research studies as the pathophysiology is poorly understood. In which gave rise to the term. Common histological descriptions
contrast, synovial sarcoma which is driven by a particular fusion which are often utilized to test knowledge of the subject in ex-
product has been studied in depth with recent findings revealing aminations include:
ORTHOPAEDICS AND TRAUMA --:- 3 Crown Copyright 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rankin KS, Basic science of musculoskeletal tumours, Orthopaedics and Trauma (2017), http://dx.doi.org/
10.1016/j.mporth.2017.03.009
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 relevant details regarding associated translocations, gene ampli-
(osteosarcoma) fications and the expression of particular cellular proteins as
malignant cells in a chondroid or myxoid matrix assessed using immunohistochemistry. Figure 5 illustrates the
(chondrosarcoma) typical EWS/FLI1 translocation found in 85% of Ewings sar-
physaliferous (leaf-like) cells (chordoma) coma cases. This fusion gene results in the production of an
chicken wire calcification (chondroblastoma) abnormal protein which is the oncodriver in Ewings sarcoma.
alphabet soup (fibrous dysplasia). Translocations are detected using fluorescent in situ hybridi-
With the development of cytogenetic and molecular di- zation (FISH) or reverse transcriptase polymerase chain reaction
agnostics, the pathology report of many lesions will include (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.
ORTHOPAEDICS AND TRAUMA --:- 4 Crown Copyright 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rankin KS, Basic science of musculoskeletal tumours, Orthopaedics and Trauma (2017), http://dx.doi.org/
10.1016/j.mporth.2017.03.009
ORTHOPAEDIC ONCOLOGY
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ORTHOPAEDICS AND TRAUMA --:- 5 Crown Copyright 2017 Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rankin KS, Basic science of musculoskeletal tumours, Orthopaedics and Trauma (2017), http://dx.doi.org/
10.1016/j.mporth.2017.03.009