Learning objective: Develop an approach to diagnosis of suspected soft tissue sarcomas in dogs and cats, including interpretation of histopathology reports. Understand the different possible surgical approaches, appropriate staging tests and indications for adjunctive treatments.

Soft tissue sarcoma (STS) is a generic term, encompassing a number of different mesenchymal tumour types. Generally, this term encompasses fibrosarcoma, peripheral nerve sheath tumour, myxosarcoma, perivascular wall tumour and liposarcoma. Tumours which are specifically excluded because they have different presentations and/or behaviour are muscle origin sarcomas, synovial sarcomas, haemangiosarcoma and lymphangiosarcoma.

Feline injection site sarcomas (FISS) are a specific subtype of soft tissue sarcoma characterised by history and location (growth at a site of previous injection), aggressive histologic features and often associated inflammation. Non-injection site-related STS in cats should be managed as for canine STS, though evidence for prognostic factors such as grade and mitotic index is lacking.

Diagnosis for all soft tissue sarcomas typically requires histopathology. Cytology may be diagnostic or at least suggestive, but especially for well-differentiated sarcomas, cannot reliably distinguish between neoplastic and reactive mesenchymal tissue. Cytology is recommended as a first step to rule out other possibilities, e.g., mast cell tumour. Histopathology may be obtained by incisional or excisional biopsy. In general, unless excision is achievable with wide margins, incisional biopsy for suspected soft tissue sarcomas should be performed to confirm the diagnosis and grade to plan the most appropriate surgery. Revision surgeries for incomplete margins following excisional biopsy are typically more extensive than what would have been required had an appropriate first surgery been performed. For suspected FISS, referral should always be recommended, as radical excision is typically required and outcomes are improved if the first surgery is aggressive. Incisional biopsy should be considered to confirm the diagnosis, but excisional biopsy is not recommended for FISS.

The important features on histopathology report for canine STS (apart from diagnosis of STS) are:

• Grade: A 3-tier scheme is typically used, based on degree of differentiation, necrosis and mitotic rate. However, the exact methodology for how these factors are assigned is not standardised and so may vary between pathologists. Grade appears to impact risk of metastasis and local recurrence, though confirming suspected metastasis or recurrence is inconsistently done in the published literature. Based on available studies, the metastatic potential is low (<15–20%) for grade 1 and 2 STS, and up to 40–50% for grade 3 STS. Histologic grade is variably prognostic for survival in the published literature (1).
• Mitotic index: What is typically reported in the veterinary literature as mitotic index should be more correctly referred to as mitotic count. However, for consistency, we will continue to use the term mitotic index (MI). MI is predictive for survival with <9/10 high power fields generally being best and >20 being worse.
• Margins: Standardised reporting of margins as ‘complete/clean’ versus ‘narrow/close’ is also lacking. Generally, any complete margin is likely sufficient for grade 1 or 2 STS - though recurrence can occur, it is very rare. Recurrence even with complete histologic margins is somewhat more common in grade 3 STS. As for mast cell tumours, the deep margin is qualitative as well as quantitative - even if narrow, if the deep margin includes fascia or muscle then this should be an effective barrier to tumour cell invasion. With narrow histologic margins (defined as <1 mm or within the tumour pseudocapsule), <10% of grade 1 tumours, approximately ⅓ of grade 2 tumours, and ¾ of grade 3 tumours recurred in one study (2), and it appears likely that recurrence rates are similar for incomplete versus close margins. However, neither margin status nor tumour recurrence have shown a definitive impact on survival time.

Within those tumours typically classified as STS, the exact histologic subtype does not seem to significantly affect prognosis, though there is some association between subtype and grade or mitotic rate. At this stage, without evidence to suggest differences in behaviour, extensive investigation to assign a specific subtype is not generally recommended once a diagnosis of STS has been confirmed.

For FISS, completeness of margins is important, with incomplete margins associated with recurrence (approximately 10x more frequently than complete margins) and with disease free interval. Because of the invasive nature of these tumours, incomplete margins are common without radical surgery.

Surgery

Whilst STSs may appear to be well encapsulated, it is the cells that are at the pseudocapsule margin that are most active. Surgery that ‘shells out’ the STS is an intralesional excision and is associated with a high local recurrence rate. STSs have microscopic projections at their periphery invading surrounding normal tissues.

Wide surgical excision is the treatment of choice for STSs. The recommended surgical margins for STSs are proportional to grade. For FISS cases, radical margins of 5 cm are recommended. It is important to obtain appropriate deep margins as well as lateral margins. The deep margin is considered a qualitative margin rather than a quantitative margin and should consist of fascia or muscle rather than adipose tissue, which is a poor anatomic barrier to tumour extension.

Low-grade STSs on the extremities present a particular situation and have been reported to be able to be managed with more marginal resections. If there is insufficient tissue for primary closure or if tension is an issue, then open wound management is reported to be successful.

Adjunctive Therapy

• Local treatment: In cases of incomplete or narrow histological margins (i.e., risk of local recurrence), additional local therapy with revision surgery or radiation therapy is recommended. However, since many incompletely or narrowly excised grade 1 or 2 STS do not recur, if clients do not wish to pursue additional therapy then ongoing monitoring is reasonable. For grade 3 tumours, the risk of local recurrence is much higher and adjunct therapy is more strongly recommended. Local chemotherapy with platinum-impregnated beads or intra-incisional 5-fluorouracil has been reported, but only in small numbers of dogs. Although recurrence rates are low, the majority are grade 1 or 2 STS and so the efficacy of these local therapies is as yet unknown, and there is some risk of toxicity.

Chemotherapy

• Metronomic chemotherapy with low dose daily oral cyclophosphamide along with daily piroxicam has been shown to significantly improve disease free interval compared to surgery alone in dogs with incompletely excised STS, however all of the tumours in the control group in this study recurred (median disease free interval of approximately 7 months), which is inconsistent with other studies (3).
• Adjuvant chemotherapy with doxorubicin is often recommended following surgery for grade 3 STS due to the risk of metastasis and is effective in improving disease-free survival in humans; however, this approach has not been proven to improve survival in canine STS.
• FISS: The combination of surgery and radiation therapy is generally accepted to be the most effective treatment. However, for tumours excised with radical surgery with wide histologic margins, adjuvant radiation may not be necessary. A recombinant canarypox virus expressing feline Il-2 (Oncept IL-2) improved tumour control in cats treated with surgery and radiation therapy in one study (4). The addition of chemotherapy (doxorubicin or epirubicin) may improve outcomes, but the true benefit is not clear.

Options for Non-resectable Tumours

• Canine STS
• Radiation therapy (RT) can be used with a definitive or palliative intent. With definitive type protocols, control rates are approximately 50% at 1 year and 33% at 2 years. Generally, radiation is used in macroscopic STS with a palliative intent, and approximately 50% respond with a median time to progression of approximately 5–10 months. One study in dogs treated with palliative RT ± metronomic chemotherapy found that the addition of metronomic chemotherapy improved survival time but not progression free interval, so the true impact is hard to determine (5).
• Chemotherapy: Doxorubicin in macroscopic STS is associated with an overall response rate of 20–30%. Mitoxantrone and ifosfamide may be effective in some dogs. Metronomic chemotherapy with chlorambucil may shrink STS or maintain stable disease in some dogs (6).
• FISS
• Palliative RT is often effective at shrinking FISS in the short term, though there is often progression within a few months. Adding chemotherapy (doxorubicin) may improve response rates and duration. Doxorubicin alone will also be effective in some cases, with response rates of 40–50%, though again these do not tend to be durable. Metronomic chemotherapy has not been. IL-2 vaccine may slow progression in unresectable feline STS (unclear if FISS were included in this abstract) (7).

References

1.  Dennis MM, McSporran KD, Bacon NJ, Schulman FY, Foster RA, Powers BE. Prognostic factors for cutaneous and subcutaneous soft tissue sarcomas in dogs. Vet Pathol. 2011;48:73–84.

2.  McSporran KD Histologic grade predicts recurrence for marginally excised ca- nine subcutaneous soft tissue sarcomas. Vet Pathol. 2009;46:928–33.

3.  Elmslie RE, Glawe P, Dow SW. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med. 2008;22:1373–1379.

4.  Jas D, Soyer C, de Fornel-Thibaud P, Oberli F, Vernes D, Guigal P-M, Poulet H, Devachelle P Adjuvant immunotherapy of feline injection-site sarcomas with the recombinant canarypox virus expressing feline interleukine-2 evaluated in a controlled monocentric clinical trial when used in association with surgery and brachytherapy. Trials in Vaccinol . 2015;4:1-8.

5.  Cancedda S, Marconato L, Meier V, Laganga P, Roos M, Leone VF, Rossi F, Rohrer Bley C Hypofractionated radiotherapy for macroscopic canine soft tissue sarcoma: A retrospective study of 50 cases treated with a 5x6 Gy protocol with or without metronomic chemotherapy. Vet Radiol Ultrasound. 2016;57:75-83.

6.  Leach TN, Childress MO, Greene SN, Mohamed AS, Moore GE, Schrempp DR, Lahrman SR, Knapp DW. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol. 2012;10:102-12.

7.  Athanasiadi I, Kaser-Hotz B, Buchholz J, Ruess-Melzer K, Herzog A. Combination of Palliative Radiation Therapy and Local Application of Oncept IL-2 (Merial) for the Treatment of Feline Soft Tissue Sarcoma (STS). Proceedings of the Veterinary Cancer Society 2016; October 20-22; Orlando FL.