Keywords
human gammaherpesvirus 8 - human immunodeficiency virus - MFS - soft tissue sarcoma
Introduction
Soft tissue sarcoma (STS) refers to a wide range of tumors of mesenchymal cell origin,
occurring anywhere in the body with a vast number of histological subtypes both benign
and malignant.[1]
[Table 1] summarizes the main subtypes sarcoma that are comprehensively described by Bansal
et al.[2] The study of STS is a constantly evolving field and regularly updated guidelines
exist to summate the most up to date evidence providing a framework against which
STS can be managed. This article will focus on imaging STS of the trunk and extremities
and will not specifically address retroperitoneal sarcoma, aggressive fibromatosis,
or neurofibromatosis.
Table 1
Selected sarcoma subtypes excluding peripheral nerve sheath tumors, gastrointestinal
stromal tumors, and chondro-osseous tumors. Adapted from article by Bansal et al[2]
|
Sarcoma subtype
|
Benign
|
Malignant
|
|
Adipocytic
|
Lipoma
Lipoma variant
|
Liposarcoma
|
|
Fibroblastic and myofibroblastic
|
Nodular fasciitis
Elastofibroma
|
Solitary fibrous tumor
Myxofibrosarcoma
Fibrosarcoma
|
|
Fibrohistiocytic tumors
|
Tenosynovial giant cell tumor
|
Malignant tenosynovial giant cell tumor
|
|
Vascular
|
Hemangioma
Epithelioid hemangioma
|
Angiosarcoma
Epithelioid hemangioendothelioma
|
|
Pericytic
|
Glomus tumor
Angioleiomyoma
|
Malignant glomus tumor
|
|
Smooth muscle
|
Leiomyoma
|
Leiomyosarcoma
|
|
Skeletal muscle
|
Rhabdomyoma
|
Rhabdomyosarcoma
|
|
Tumors of uncertain differentiation
|
Myxoma
Angiomyolipoma
|
Synovial sarcoma
Alveolar soft part sarcoma
Clear cell sarcoma
Undifferentiated pleomorphic Sarcoma
Undifferentiated spindle cell sarcoma
|
|
Neural
|
Schwannoma
Neurofibroma
|
Malignant peripheral nerve sheath tumor
|
Risk Factors and Etiopathogenesis
As with most malignancies, there is no single causative factor for STS. Instead, the
etiology is multifactorial with both genetic and environmental factors known to increase
the risk of disease. These factors include viral infections (human gammaherpesvirus
8 and human immunodeficiency virus), previous radiation therapy, chronic lymphoedema,
and environmental carcinogens. Several genetic conditions including but not limited
to Li-Fraumeni syndrome, neurofibromatosis-1, and Gardner syndrome are also known
to increase the risk.[3]
[4]
[5]
Epidemiology and Clinical Presentation
The disease is rare making up approximately 1% of adult and 15% of childhood malignancies
and in 75% of cases occurs in the extremities.[3]
[4] The clinical presentation is variable but is typically of a growing soft tissue
lump that in some cases may have been present for many years. Constitutional symptoms
(weight loss, fever, etc.) are rare but can occur and the disease will often present
late.[6]
Imaging Referral Guidelines
The referral for investigation of STS is of paramount importance to ensure that the
correct diagnosis can be obtained and appropriate treatment initiated as soon as possible.
Patients (both children and adults) should be urgently referred for further investigation
in all suspicious soft tissue lumps.[7] The referral pathway utilised at the authors institution is summarized in [Fig. 1].
Fig. 1 A simplified referral pathway utilized by the authors institution in combination
with relevant recommendations in the literature.
Imaging plays a central role in the workup of STS in terms of early diagnosis, through
assessment of treatment response and monitoring for disease recurrence. The choice
of initial investigation will depend on clinical factors including site of concern
and examination findings. In general, investigation of the head, neck, mediastinum,
and retroperitoneum is best served by computed tomography (CT), while ultrasound is
considered the optimum initial investigation for clinically palpable lesions. This
is reflected in several guidelines that recommended ultrasound as the initial investigation.[1]
[2]
[8] Plain radiographs also have a role in the workup particularly in lesions affecting
the extremities. Magnetic resonance imaging (MRI) is considered the gold standard
investigation; however, its role as an initial investigation is not supported and
instead it is used to further and more accurately characterize lesions.[2]
[9]
Clinical/ Diagnostic work-up Excluding Imaging
The variable presentation of sarcoma coupled with its rarity and heterogeneity as
a disease entity poses a diagnostic challenge for the clinician at the time of patient
presentation. While almost all cases will require imaging to further investigate,
it is important to remember that the vast majority will be benign.[1]
[10]
[11] A detailed clinical history and thorough clinical examination should therefore be
performed to triage those cases in which there is a higher suspicion of malignancy.
This will enable appropriate onward referral.[7] The clinical history should detail the site, pain symptoms, duration of lump, and
any history of malignancy or previous surgery. Further information on the rate of
growth and any associated symptoms should also be elucidated. Examination should confirm
the size, depth, consistency, mobility, skin alterations, and presence of lesions
elsewhere as well as confirm the presence or absence of tenderness. Clinical findings
that raise the concern of malignancy include but are not limited to a size of more
than 5cm, pain/tenderness, and lesion growth.[10]
[11]
Imaging Guidelines
Screening
There is no specific screening program for STS. While in some conditions known to
increase the risk—such as Li-Fraumeni syndrome—there may be specific individualized
guidance in relation to the detection of malignancy; the broad aim is to encourage
early presentation at the development of concerning symptoms.[4]
[12]
Diagnosis
As already discussed, imaging is a fundamental component of patient workup for STS
and essentially all patients will undergo some form of radiological investigation.
The full range of modalities can be utilized, ranging from traditional plain film
radiography to newer and less well-established techniques such as positron emission
tomography/magnetic resonance imaging (PET/MRI). Imaging can be considered in terms
of the advantages and disadvantages of the specific modality in question, the clinical
presentation, and also the histological subtype of sarcoma that will determine the
disease course.[2]
[9]
[13] Detailed below is a summary of the commonly used modalities and their role in the
investigation of STS.
Plain radiographs are a cheap and widely available test that can be of use in the
initial workup of a soft tissue lump—indeed the American College of Radiologists recommend
them as part of the initial evaluation of a superficial lesion.[9] They are, however, limited by poor soft tissue contrast. For this reason, use is
limited to the assessment of any relevant bony or mineralization changes at the site
of concern (e.g., periosteal reaction, bony destruction). In certain situations, they
may provide a diagnosis or significantly narrow the differential such as a lump corresponding
to normal bony anatomy or reveal the presence of phleboliths indicating a hemangiomatous
lesion.[14]
[15]
Ultrasound has been shown to be an effective investigation for the initial evaluation
of a soft tissue lump.[16]
[17] In contrast to plain radiographs, ultrasound provides good soft tissue resolution
and is a useful triage test to differentiate benign pathology such as simple lipomas,
ganglion cysts, muscle hernias, and uncomplicated vascular malformations from more
sinister lesions.[11]
[17] The easy access of ultrasound to most primary care physicians has the advantage
of providing patients reassurance and reducing the referral burden on local tertiary
referral centers.[10] It is, however, limited by several factors, including but not limited to operator
experience and patient body habitus. Location is also an important factor to consider
as deeper lesions tend not to be easily amenable to assessment, particularly when
a large geographical body area is required to be assessed. Similarly, bony lesions/bony
involvement is not easily assessed.[17]
[18]
MRI provides high spatial resolution, optimum soft tissue contrast, and allows accurate
assessment of not just lesion size and morphology but also the relationship of the
lesion to other structures (including local neurovasculature anatomy) enabling accurate
local staging.[9]
[13] Studies have assessed the utility of MRI in predicting the eventual grade of lesion
and clinical outcome.[19]
[20]
[21]
[22]
[23] Crombé et al found that MRI features of tumor necrosis, heterogeneity, and peritumoral
enhancement were associated with higher grade lesions. They also found that two or
more of these features in combination were associated with a worse metastasis-free
survival (MFS) as well as overall survival (OS). Interestingly, when the same principle
of the presence of two or more of these features was applied to lower grade lesions
(1 and 2), the MFS and OS were the same as for grade 3 lesions with the authors surmising
that these MRI features could be used to predict prognosis on the baseline scan.[19] Other features that have been found to correlate with poor outcomes include lesion
heterogeneity and size more than 10cm (in all STS subtypes) as well as features specific
to individual sarcoma subtypes of which there are several. Scalas et al comprehensively
describe several of these features which include the tail sign adjacent to the lesion
in undifferentiated pleomorphic sarcoma and myxofibrosarcoma and the so-called triple
sign in synovial sarcoma. This reflects the presence of low, intermediate, and high
signal within the lesion. These features and others are summarized in [Table 2] along with their significance.[13]
[20]
[21]
[24]
Table 2
MRI findings associated with specific sarcoma subtypes. Adapted from article by Scalas
et al[13]
[20]
[21]
[24]
|
Sign
|
Sarcoma subtype
|
Significance
|
|
Tail sign
|
Undifferentiated pleomorphic sarcoma, myxofibrosarcoma
|
Higher risk of local recurrence and distant metastases at diagnosis
|
|
Water like appearance
|
Myxofibrosarcoma
|
Increased likelihood of local recurrence with increasing percentage of water like
signal within lesion
|
|
Triple sign
|
Synovial sarcoma
|
Reduced disease-free survival
|
|
Absence of calcifications
|
Synovial sarcoma
|
Reduced disease-free survival
|
|
Signal heterogeneity
|
Myxoid liposarcoma
|
High-grade lesions and poorer prognosis
|
CT can be useful in patients unable to undergo MRI assessment (e.g., incompatible
pacemakers and severe claustrophobia) or in cases where plain radiographs are unlikely
to provide sufficient information on bony anatomy, bony involvement, or matrix mineralization.[9]
[14] Indeed, a historic study by Panicek et al acknowledged the superior soft tissue
contrast of MRI over CT; however, it did not show an advantage of MRI over CT for
local staging translating into improved clinical outcomes.[25] It is worth considering that this study was performed over two decades ago and it
is at least theoretically possible that with improved imaging techniques, the results
could be different were a similar more up to date study performed. It is, therefore,
the author's view that every effort should be made to perform an MRI where possible.
FDG-PET-CT is a well-established investigation for the workup of many malignancies.
However, its role in the assessment of STS is less so. Several studies have assessed
its utility in the workup of STS specifically in terms of the ability to predict tumor
behavior and prognosis.[26]
[27]
[28]
[29]
[30] Generally, higher maximum standardized uptake value values have tended to correlate
with higher grade disease/malignant disease.[26]
[27]
[28] Caution is, however, advised as there are several limitations, including the low
uptake of fluorodeoxyglucose (FDG) in certain tumor subtypes including myxoid liposarcoma
and synovial sarcoma that inherently limit the application of PET in these specific
subtypes.[26] Conversely, there is also a considerable issue of false positives that may arise
as the result of inflammatory pathology and benign soft tissue lesions that are FDG
avid.[27]
[28] Irrespective of these limitations, FDG-PET-CT has been shown to lead to a change
in management in a not insignificant number of patients as demonstrated by Lee et
al, although this was not necessarily in direct relation to the known diagnosis of
STS.[29]
Percutaneous biopsy is the standard/preferred method by which to obtain a definitive
diagnosis. Although this is now a well-established technique, there are pitfalls that
the clinician must be aware of including the potential for under grading the lesion.
It is recognized that lesions may harbor areas of higher-grade tumor or dedifferentiation
that the biopsy can miss.[24] For obvious reasons this may have significant treatment repercussions and may only
come to light on subsequent analysis of a surgically excised lesion at which point
the tumor is upgraded. To gain as representative sample as possible, it is, therefore,
recommended that the biopsy be undertaken by a clinician experienced in sarcoma imaging,
usually a radiologist. In addition, guidelines suggest planning the biopsy in conjunction
with the operative surgeon such that the biopsy tract can be excised to reduce the
likelihood of tumor seeding. While this is common practice, there seems to be relatively
little evidence base for this in the literature.[31] In cases where a percutaneous biopsy is either not possible (e.g., due to anatomical
constraints) or has failed, open biopsy can be performed. Small (typically <3cm) lesions
can be considered for excisional biopsy.[1]
[4]
[8]
[32]
Staging
The staging of STS typically follows the American Joint Committee on Cancer (8th edition)
guidelines. This provides a tumor, node, and metastasis (TNM) classification, according
to lesion size, nodal involvement and distant metastases. The Fédération Nationale
des Centres de Lutte Contre Le Cancer (FNCLCC) criteria take into account tumor differentiation,
mitotic activity, and extent of necrosis to provide a tumor grade. The TNM score and
the tumor grade are used in combination to assign disease stage (I–IV).[33] The approach to staging in terms of imaging will vary somewhat depending on the
histology of the tumor. Typical staging consists of CT chest for STS and others include
CT abdomen and pelvis for myxoid liposarcoma, and central nervous system imaging is
usually performed in cases of alveolar soft part and also clear cell sarcoma as a
result of a higher likelihood of metastatic disease to these regions, respectively.[1]
[8] Whole body MRI is recommended as part of staging for myxoid liposarcomas due to
the possibility of bone metastasis.
Follow-Up
The follow-up of STS is important given the risk of local recurrence (LR) and of distant
metastases. While there is no universally agreed regimen, in practice this usually
combines clinical examination, imaging to assess the site of primary tumor, and a
chest X-ray (CXR) or CT chest to exclude metastatic disease (the lungs being the most
common site). It is also important to consider the original grade of tumor as local
recurrence is more likely with the higher-grade lesions. It is, therefore, reasonable
to follow up such groups more aggressively and this is reflected in various guidelines.
Typically, lower grade lesions can be followed up with yearly clinical exam ± MRI,
while higher grade lesions are followed up more regularly—intervals ranging from 3
to 6 months initially and gradually tapered down if no recurrent disease is discovered.
Particular attention is paid to the first 2 to 3 years, where the risk of recurrence
is at its highest with the risk of recurrence after 10 years considered small.[1]
[4]
[8] It is worth noting that there is dubiety as to the value of imaging follow-up versus
clinical examination. Rothermundt et al demonstrated that most local recurrences were
picked up clinically, either by the patient or physician on follow-up.[34] However, more recent studies have shown improved detection of LR with the use of
MRI versus clinical examination alone.[35]
[36] The role of CT over CXR has also been questioned in the detection of pulmonary metastases
with a study by Puri et al showing that the use of CT neither conferred a survival
advantage nor an improvement in the detection of pulmonary metastatic disease.[37]
Principles of Management
As emphasized in all major guidelines, the cornerstone of good sarcoma care is management
through a dedicated and formalized multidisciplinary team meeting. This enables a
team of professionals including but not limited to surgeons, oncologists, radiologists,
and specialist nurse practitioners to gain sufficient exposure to this rare disease
to be in a position to offer the latest evidence-based care to patients. A detailed
discussion on the treatment of STS is beyond the scope of this article, but the standard
treatment is surgical excision for localized disease. Supplementary therapies are
often given and in particular pre/postoperative radiotherapy. Chemotherapy has a role
in certain chemosensitive subtypes but in general its use is limited in STS. The specific
therapy offered to patients depends on a vast array of factors including histological
subtype, amenability to resection, grade of tumor, co-morbid status/goals of therapy,
lesion size, and anatomical location. The management of recurrent disease depends
of whether this is localized or metastatic with palliative care often appropriate
in the latter. This may take the form of best supportive care, or in specific scenarios
ablation/embolization procedures or metastasectomy as appropriate.[1]
[4]
[8]
[Fig. 2] summarizes the main points in relation to the management of STS according to the
UK, US, and European guidelines for illustrative purposes only.[1]
[4]
[8] The reader is advised to refer directly to local guidance according to their area
of practice.
Fig. 2 Summarized flow chart showing the broad principles of management as per the UK, EU
and US guidelines.
