Just diagnosed a veterinary patient with soft tissue sarcoma? Read on! Today’s VETgirl online veterinary continuing education blog is by guest blogger Dr. Christine Mullin, VMD, Diplomate ACVIM (Oncology), Hope Veterinary Specialists.
Canine soft tissue sarcomas – not just a dime a dozen
Soft tissue sarcomas (STS) account for approximately 15-20% of all skin and subcutaneous tumors in the dog.1-2 STS are a heterogeneous collection of tumors and are composed of the mesenchymal cells that constitute the various forms of connective tissue. Each different type of STS is named for the tissue of origin, such as fibrous, nerve sheath, adipose, and muscle tissue. Specific examples of STS subtypes include fibrosarcoma, hemangiopericytoma (aka malignant peripheral nerve sheath tumor, formerly Schwannoma), liposarcoma, myxosarcoma, rhabdomyosarcoma, and undifferentiated sarcoma.1-3 Sometimes it is not possible to differentiate the subtype of a sarcoma, and so the general term STS or spindle cell tumor/sarcoma is applied. Other sarcomas typically considered as separate entities outside of the STS group include hemangiosarcoma, lymphangiosarcoma, histiocytic sarcoma, synovial cell sarcoma, and leiyomyosarcoma.1
STS are associated with two main challenges: 1) often deceptively invasive primary tumor growth (“tip of the iceberg” phenomenon), and 2) a variable risk for systemic metastasis, particularly to the lungs. The biologic behavior and expected prognosis for canine STS is highly dependent upon tumor grade, which is based on the following histologic features: degree of differentiation, mitotic index, and percentage of necrosis. There is a grading scheme which assigns a numerical score (1, 2, or 3) based on the degree of abnormality within each of those categories; the numerical values for each of the three features are then added together and this sum then determines whether the tumor is a grade I (low), grade II (intermediate), or grade III (high).1 Additional factors that may influence tumor behavior, diagnostic recommendations, and therapeutic approach include tumor size, rate of clinical growth, and tumor location.1-3 Upon diagnosis, patients typically undergo a series of tests (“staging”) including lab work, fine needle aspirate cytology and/or biopsy, and imaging (radiographs, ultrasound, +/- CT scan/MRI) to help determine the nature and extent (“stage”) of their disease.
Standard of care therapy for localized STS is centered upon wide margin surgical excision, which entails 3 cm lateral margins and an in tact deep fascial layer. Sometimes such an approach requires major tissue resection, skin flaps, tissue grafts, or amputation. Low and intermediate grade tumors can often be cured with complete excision, as the risk of these tumors recurring is extremely low and the chance for metastasis is similarly quite modest. In these scenarios, no further therapy is recommended after complete excision and dogs are simply monitored going forward. On the other hand, dogs that undergo removal of a grade III STS are often treated with follow up chemotherapy because of the considerable risk (41-44%) of metastasis for this category of tumors3-4. Although no study has demonstrated a true benefit from adjuvant chemotherapy following removal of high grade STS, principles of cancer therapy suggest that some additional therapy is warranted and as such, most oncologists will recommend a Doxorubicin-based protocol for these patients. The median time to develop lung metastasis is reported as anywhere from 8 months to 1 year,3,5 thus periodic (every 3-6 months) follow up thoracic radiographs are recommended for these patients on a long-term basis. The median survival time for dogs with grade III STS undergoing surgery +/- chemotherapy is > 2 years, thus even “aggressive” STS are quite treatable.4
Although surgical removal is effective at reducing the patient’s burden of disease, histologic margins are often narrow or incomplete due to the invasive nature of STS. Following incomplete STS excision, there is a risk of local tumor recurrence that is dependent on tumor grade. Specifically, there is a 7%, 34%, and 75% risk of local tumor recurrence following marginal/incomplete excision of grade I, II, and III STS, respectively.7 There is some discrepancy amongst veterinary studies in how to categorize a tumor as “narrowly”, “marginally”, or “incompletely” excised, however, most oncologists designate tumors with
When considering additional local therapy options, although scar revision surgeries (removal of 2-3 cm around and 1 fascial plane below the initial incision) are effective at reducing the risk of tumor regrowth following incomplete excision, they are often not feasible because of tumor location (e.g. a distal limb with very little excess skin available). Undoubtedly, an aggressive surgery such as amputation would have a high chance of curing such a patient. However, although we as attending oncologists always want to do what is most medically appropriate for the tumor, we also have to weigh what negative consequences intensive therapy may have on the patient. For example, is that incompletely excised grade II STS of the distal limb life-threatening enough to warrant amputating the leg of that arthritic geriatric dog (a quality of life-threatening measure)?…Similarly, is it worth putting that same dog through labor-intensive full course radiation therapy (18 daily treatments under general anesthesia) – albeit a highly effective alternative for controlling incompletely excised STS long-term5,8,9 – when the risk of the tumor growing back in that old dog’s lifetime is only 1 in 3?7 To further muddy the waters, some studies have shown an even lower risk of recurrence of incompletely excised distal limb STS,10-11 therefore maybe odds are that nothing more needs to be done. However, if we do nothing and a tumor does recur along a tough area like the distal limb, treatment options become even more limited down the line. These are the decisions and scenarios we struggle with as veterinary oncologists managing the various presentations of canine STS.
Fortunately, we also have more conservative options at our disposal, such as metronomic (low dose daily oral) chemotherapy and the always available “watch, wait and see” approach. Metronomic chemotherapy, which involves the use of low dose daily oral therapy with either cyclophosphamide (Cytoxan) or chlorambucil (Leukeran), typically along with a non-steroidal anti-inflammatory drug (NSAID), is a nice lower intensity option for patients such as the one described above. Preferred in the setting of microscopic residual disease, metronomic chemotherapy focuses on disrupting the vascular environment so that dormant tumor cells do not gain the blood supply needed to grow (antiangiogenenic therapy). Metronomic chemotherapy has also been shown to have immunomodulatory effects that help the body detect and eradicate tumor cells. A study evaluating the use of metronomic Cytoxan and piroxicam as adjuvant to incompletely excised grade II STS in dogs showed that the addition of this therapy significantly increased the time before which the tumor recurred, and so has become a popular “go-to” option for dogs that are not great candidates for the more intensive therapies.12-13
Finally, for STS that are not amenable to surgical resection, palliative radiation therapy can be considered as a means to provide improved comfort and partial tumor regression. The objective response rate for RT in this setting is roughly 50%, for a median tumor control duration of ~5 months.14 This therapy is typically given once weekly for 4 treatments and side effects are rare, although treatments do require general anesthesia.
As outlined above, the continued advances made on both the human and veterinary oncology fronts have shown us that are not all tumors are created equal. Thus, a personalized approach that is based upon the entire constellation of tumor- and patient-related characteristics is more appropriate than simply assigning a “one size fits all” formula for treatment.
1. Liptak JM and Forrest LJ. Soft tissue sarcomas. In: Small Animal Clinical Oncology. 5th edn., SJ Withrow, DM Vail, Page RL, Eds., St. Louis, Saunders/Elsevier, 2013:356-380.
2. Hohenhaus AE, Kelsey JL, Haddad J, et al. Canine cutaneous and subcutaneous soft tissue sarcoma: An evidence-based review of case management. J Am Anim Hosp 2016;52(2):77-89.
3. Kuntz CA, Dernell WS, Powers BE, et al: Prognostic factors for surgical treatment of soft tissue sarcomas in dogs: 75 cases (1986–1996). J Am Vet Med Assoc 1997;211: 1147–1151.
4. Selting KA, Powers BE, Thompson LJ, et al. Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996-2004). J Am Vet Med Assoc 2005;227:1442-1448.
5. Simon D, Ruslander DM, Rassnick KM, Wood CA, et al: Orthovoltage radiation and weekly low dose of doxorubicin for the treatment of incompletely excised soft-tissue sarcomas in 39 dogs. Vet Rec 2007;160:312–326.
6. Bacon NJ, Dernell WS, Ehrhart N, et al. Evaluation of primary re-excision after recent inadequate resection of soft tissue sarcomas in dogs: 41 cases (1999-2004). J Am Vet Med Assoc 2007;230:548-554.
7. McSporran KD. Histologic grade predicts recurrence for marginally excised canine subcutaneous soft tissue sarcomas. Vet Pathol 2009;46:928–933.
8. McKnight JA, Mauldin N, McEntee MC, et al: Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. J Am Vet Med Assoc 2000;217:205–210.
9. Forrest LJ, Chun R, Adams WM, et al. Postoperative Radiotherapy for Canine Soft Tissue Sarcoma. J Vet Intern Med 2000;14:578–582.
10. Stefanello D, Morello E, Roccobianca P, et al. Marginal Excision of Low-Grade Spindle Cell Sarcoma of Canine Extremities: 35 Dogs (1996-2006). Vet Surg 2008;37:461-465.
11. Prpich CY, Santamaria AC, Simcock JO, et al. Second intention healing after wide local excision of soft tissue sarcomas in the distal aspects of the limbs in dogs: 31 cases (2005-2012). J Am Vet Med Assoc 2014;244:187-194.
12. 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.
13. Burton JH, Mitchell L, Thamm SW, et al. Low-Dose Cyclophosphamide Selectively Decreases Regulatory T Cells and Inhibits Angiogenesis in Dogs with Soft Tissue Sarcoma. J Vet Int Med 2011;25:920-926.
14. Lawrence J, Forrest L, Adams W, et al. Four-fraction radiation therapy for macroscopic soft tissue sarcomas in 16 dogs. J Am Anim Hosp 2008;44(3):100-108.