Soft tissue sarcomas (STS) arise from the neoplastic transformation of mesenchymal cells and comprise around 15 percent of all skin and subcutaneous tumours in dogs (Theilen and Madewell, 1979). They can arise in muscle, adipose, neurovascular, fascial and fibrous tissues but most commonly involve the skin and subcutis. As well as occurring naturally, STS can develop secondary to radiation exposure, trauma, foreign bodies, implants and parasitic infection (Spirocerca lupi) (Liptak and Christensen, 2019).
The term “soft tissue sarcoma” encompasses a variety of specific tumour subtypes classified together as STS due to similar pathological appearance, clinical behaviour and treatment approach. Certain sarcomas are excluded from the “STS” classification due to differences in anatomical location, histological features and biological behaviour. The common tumour subtypes included in the STS classification are fibrosarcoma, perivascular wall tumour, peripheral nerve sheath tumour (non-brachial/lumbar plexi), liposarcoma and myxosarcoma.
The term “soft tissue sarcoma” encompasses a variety of specific tumour subtypes classified together as STS due to similar pathological appearance, clinical behaviour and treatment approach
Most STS in dogs have a similar clinical presentation and biological behaviour, which is characterised by a locally expansive to infiltrative soft tissue mass. A pseudocapsule comprising compressed peritumoral connective tissue is also commonly present. Generally, recurrence rates following surgery are low to moderate, and the overall metastatic risk is low. However, these risks vary depending on factors such as tumour grade and subtype and will be discussed in more detail later in this article.
History and clinical signs
Most STS present as slow-growing cutaneous or subcutaneous masses over the extremities or flanks. Occasionally (especially in high-grade STS), growth can be more rapid, and ulceration can occur. Most dogs present asymptomatically, although clinical signs associated with the tumour depend on location and size. Different STS presentations are highlighted in Figure 1.
Diagnosis and staging
As with most cutaneous and subcutaneous masses, fine needle aspirate cytology is initially indicated for diagnosis. However, poor cell exfoliation in STS can make definitive diagnosis challenging. Cytology may be non-diagnostic or only “suggestive” of STS but should at least rule out round cell or epithelial tumours. Biopsy for histopathology may, therefore, be required for definitive preoperative diagnosis.
Unless the mass is small and easy to excise with wide lateral and deep margins, excisional biopsy is not advised. Biopsies should instead be obtained by needle-core, punch or incisional methods, ensuring that the biopsy tract can be removed along with the tumour at the time of surgery.
In addition to achieving a definitive diagnosis, biopsy and subsequent histopathology should also be able to provide the tumour grade, which can aid decision making regarding further investigations and treatment. It should be noted, however, that preoperative biopsies underestimate and overestimate tumour grade in around 30 percent and 10 percent of cases, respectively (Perry et al., 2014).
Soft tissue sarcomas are classified as either low grade (grade I), intermediate grade (grade II) or high grade (grade III) based on the degree of cellular differentiation, mitotic index and percentage necrosis (Dennis et al., 2011).
Further testing
Once STS is confirmed, further investigations should be undertaken prior to treatment. Initially, a minimum database consisting of haematology, biochemistry and urinalysis should be performed.
If canine STS metastasise, it is typically via haematogenous spread to the lungs, with lymph node (LN) metastasis less common. Therefore, assessment of the lungs is most important and should ideally be performed in all cases. Methods include three-view inflated thoracic radiographs and computed tomography (CT). The latter is ideal as it is more sensitive at detecting smaller pulmonary nodules.
Advanced imaging of the primary tumour should also be considered alongside staging, especially for tumours in difficult locations where surgical excision will be challenging
Fine needle aspirates of draining/sentinel LNs are mostly performed for high-grade STS or those with enlarged LNs. Tumour grade may help guide the staging approach; for reference, the metastatic rates for low-, intermediate- and high-grade STS are 0 to 13 percent, 7 to 27 percent and 22 to 44 percent, respectively (Ettinger et al., 2006; Kuntz et al., 1997; Selting et al., 2005).
Advanced imaging (eg CT) of the primary tumour should also be considered alongside staging, especially for tumours in difficult locations where surgical excision will be challenging, as it may aid the planning of surgical margins.
Treatment and prognosis
Local tumour control is the most important aspect of STS management. Surgical resection is therefore the preferred treatment modality where possible. Adjuvant therapies such as radiation therapy (RT), electrochemotherapy (ECT) or chemotherapy can be used in cases of incomplete excision, and these modalities can also have a role in the macroscopic disease setting.
Surgery
Wide surgical excision of STS gives the highest chance of complete excision and long-term tumour control, so resection with adequate margins is imperative (Baker-Gabb et al., 2003). Generally, excision with 2 to 3cm lateral margins and one fascial plane deep to the tumour is recommended. However, this is not always possible due to factors such as tumour size and location, and in some cases, only a marginal excision will be possible.
As validated for canine mast cell tumours, a proportional margin system wherein a lateral margin equal to the tumour diameter is used could also be considered for STS (Pratschke et al., 2013). For very large and/or invasive STS (Figure 2), more radical resection or amputation may be needed, although factors such as tumour grade will influence decisions regarding surgical dose. If a low to intermediate-grade STS has been completely excised, often no further treatment is indicated. Instead, active monitoring consisting of scar and regional LN palpation should be performed on a three-monthly basis.
Median survival times following surgery alone range between 2.5 and 5 years and are often not reached in many studies (Liptak and Christensen, 2019). For high-grade STS, adjuvant maximum tolerated dose (MTD) chemotherapy should be considered even if completely excised (discussed further below). A median survival time of around two years was reported in one study (Selting et al., 2005). A variety of adjuvant therapies may be used following incomplete excision of STS and are explored in the following section.
Adjuvant therapy
Incompletely excised STS can recur, with the risk mostly dependent on tumour grade. Recurrence rates are around 7 percent, 34 percent and 75 percent for low-, intermediate- and high-grade STS, respectively (McSporran, 2009).
Active monitoring could be considered in low-grade STS if owners are aware of the recurrence risk and the location is amenable to further treatment should recurrence occur. This could also be appropriate for some intermediate-grade STS, although the risk of recurrence is moderate in these cases (34 percent).
If the surgical scar is amenable to re-excision, then wide resection of the scar with the same margin recommendations as primary STS could be considered. Interestingly, it should be noted that only 22 percent of scars from incompletely excised STS had histological evidence of residual disease in one study (Bacon et al., 2007).
Radiation therapy
Where revision surgery is not possible, adjuvant RT is the preferred treatment approach for incompletely excised STS due to its established role in the management of human STS and the evidence of its benefits in the veterinary literature.
Definitive-intent (hyperfractionated) protocols are generally advised to minimise the risk of late adverse effects, and total doses of over 50Gy are recommended (Forrest et al., 2000).
Where revision surgery is not possible, adjuvant radiation therapy is the preferred treatment approach for incompletely excised soft tissue sarcomas
Most of the canine literature regarding adjuvant RT for STS is retrospective and dated but report recurrence rates in around 15 to 35 percent of dogs, with four-year local control rates up to 81 percent. Median time to local recurrence can be prolonged (one to five years), with median survival over six years for low/intermediate-grade STS and high-grade STS recurring more rapidly (2.5 to 10 months) (Liptak and Christensen, 2019).
Electro- and metronomic chemotherapy
If RT is not feasible, adjuvant ECT or metronomic chemotherapy with cyclophosphamide are alternative options.
Electrochemotherapy involves the administration of bleomycin or cisplatin intratumorally or systemically before administering electrical pulses to the tumour/scar tissue, which increases cellular uptake of the drugs. Recurrence rates between 12 and 36 percent have been reported following ECT treatment of incompletely excised canine STS (36 percent recurrence rate was for high-grade STS) (Spugnini et al., 2019, 2007).
Metronomic chemotherapy involves the low-dose daily administration of alkylating agents, such as cyclophosphamide, alongside non-steroidal anti-inflammatories to promote anti-tumour immunity and inhibit angiogenesis. It is often very well tolerated and has been shown to prolong disease-free intervals in dogs with incompletely excised STS (Burton et al., 2011; Elmslie et al., 2008).
MTD chemotherapy
The role of MTD chemotherapy is currently unclear and is not typically administered in most cases of STS. Doxorubicin can be considered in high-grade STS where the metastatic rate is reported up to 44 percent; however, although some individual patients may benefit, there is no clear evidence of benefit across the wider population (Selting et al., 2005).
Management of non-surgical cases
Radiation therapy can be used alone in non-surgical STS. Response rates up to 50 percent have been reported, although the duration of response is often relatively short. One- and two-year control rates of 50 percent and 33 percent have been reported, respectively; hyperfractionated and hypofractionated protocols seem to have similar outcomes (Liptak and Christensen, 2019).
Electrochemotherapy has been reported in a very small number of dogs with macroscopic STS, with 75 percent of cases achieving a complete or partial response to treatment (Torrigiani et al., 2019).
