Soft tissue sarcomas of the distal limb – could “less be more”?

Case report: August is an 11 year old female spayed Labradoodle that presented to the oncology service for consultation regarding a recently diagnosed soft tissue sarcoma. A semi-firm soft tissue mass was noted along the cranial aspect of her right distal radius and was thought to have shown moderate growth to a size of approximately 3-4 cm over the previous 4-5 months. She also had several other dermal and subcutaneous masses that were softer and previously diagnosed as lipomas. The right forelimb mass was marginally excised by her primary veterinarian and histologic evaluation of submitted tissue was consistent with an incompletely excised (both lateral and deep margins) grade II (mild to moderate anisocytosis/anisokaryosis, mitotic index = 7, <50% necrosis) soft tissue sarcoma (STS), thought most consistent with a hemangiopericytoma. At surgery, the mass was noted to have ill-defined deep extension that was adherent to the underlying tendons.

At oncology consultation, the incision was well healed and she appeared otherwise healthy aside from generally decreased mobility. Full blood work (CBC/Chemistry) was unremarkable and three-view thoracic radiographs were free of pulmonary metastatic disease. In light of the residual local disease following initial surgery, a discussion was had regarding the available options for follow up therapy, which included:

  1. Curative intent surgery (right forelimb amputation)
  2. Full course radiation therapy
  3. Conservative surgery (scar revision)
  4. Metronomic chemotherapy
  5. Monitoring without further therapy

The reported risk of local recurrence for marginally excised grade II STS is 34%1, therefore an incompletely excised tumor of this grade would be predicted to have an equal to or even higher risk of regrowth. The metastatic rate of grade II tumors is somewhat unclear, but reported to be anywhere from 7% to 33% across studies2-5, although it’s generally accepted that it’s more likely toward the lower end of that range (<20%). Therefore, less priority was given to therapeutically addressing the modest risk of metastasis for August’s tumor. However, additional local therapy was recommended.

Because of August’s age and concurrent orthopedic disease, as well as the recognition that local tumor regrowth was possible not a guarantee, an aggressive approach with full limb amputation was considered an over-treatment in this case, although it would certainly have the best chance at completely eradicating her residual disease. The next most aggressive adjuvant treatment option, full course radiation therapy, is also quite effective, with one study finding the rate of local control at 3 years to be 85% with the combination of surgery and adjuvant radiation, although 31% of dogs still had local tumor recurrence6. Another study found just a 17% risk of tumor regrowth with a median time to local tumor recurrence of 700 days7 after radiation for incompletely excised STS. However, the requirement for 15-18 consecutive daily anesthetic events for this therapy made adjuvant radiation an unfavorable option for this particular owner and dog.

The third option reviewed was the possibility for a second surgery that would be aimed at removing as much tissue around and underneath the scar as possible. The standard approach would be to remove 2-3 cm of normal tissue around the lateral margin and an intact fascial plane deep, but this is not always possible, especially with a second surgery. Evidence to suggest that re-excision surgery might be a favorable option for August stems from a 2008 study8 that examined the outcomes of dogs undergoing marginal excision of low-grade spindle cell sarcoma of the extremities. In this study, about 30% of dogs had clean excision, ~30% were clean but close, and ~30% of tumors had dirty margins. However, the local recurrence rate was only 10.8%. Thus, even if only narrow margins were achieved with a second surgery, it would likely lower August’s risk of local tumor recurrence overall.

It was discussed that there were a few possible disadvantages to this surgical approach. First, achieving clean margins may not be possible given the reported invasiveness of this tumor, particularly at the deep margin. This information would not be determined until the final biopsy report became available. Interestingly, a 2007 JAVMA study9 examined the outcomes of dogs undergoing primary re-excision after incomplete resection of soft tissue sarcomas and found that even though all tumors were initially incompletely excised (and thus should have contained residual tumor at the surgery site), only 22% had residual tumor identified in the second biopsy sample. This might be due to a couple of reasons. First, it can be difficult to identify small populations of residual neoplastic mesenchymal cells in beds of active granulation tissue, which are also composed of mesenchymal cells (fibroblasts). Additionally, in veterinary pathology, only a few sections (typically 4 or less) are typically examined as part of histologic analysis, and thus foci of residual tumor cells could be overlooked in a large biopsy. The local recurrence rate following a second surgery in the Bacon et al. JAVMA study was just 15%. The authors argued that a major advantage of such an approach is that for most dogs, a favorable long-term outcome was achieved without radiation therapy or amputation. Fifty-one percent (51%) of dogs in this study had their tumor located on a limb, like August.

A second possible disadvantage to a scar revision surgery was that secondary surgeries in this region sometimes leave an open wound that requires healing by second intention and even skin grafts because of the scarcity of excess tissue available for surgical wound closure.  Nevertheless, a recent study10 evaluated second intention healing after wide local excision of soft tissue sarcomas in the distal aspects of the limbs of dogs and found that 93.5% of the wounds healed completely by second intention over a median time of 53 days, while just 6.5% of dogs required a free skin graft. Only 3.2% of dogs developed local tumor recurrence.  The rates of short-term and long-term complications of wound healing were modest (22.6% and 9.7%, respectively) and all were managed conservatively.

For August, a scar revision surgery was elected and went without complication. Lateral margins of 2 cm were obtained along with resection of as much deep tissue as was possible without disrupting the normal tendon anatomy; en bloc resection of an intact fascial plane was not feasible because the deep tissue was already disturbed from the initial surgery. Fortunately, primary incisional closure was achieved.  Histologic evaluation confirmed residual grade II STS (peripheral nerve sheath origin – i.e. hemangiopericytoma) with a low mitotic rate, but this time the lateral margins were clean by 4-5 mm and only the deep margin was considered incomplete in a few areas where cells extended to the edge of the section. August recovered very well and owner was pleased with the cosmetic and functional outcome of the second surgery. Although her tumor was still not completely excised, the second surgery was considered successful because it eradicated residual tumor that was large enough to be detected microscopically, and thus was likely enough to have led to local tumor regrowth if further therapy had not been pursued.

Following healing from the second surgery, adjuvant therapy was discussed and priority was given to 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).  Preferred in the setting of microscopic residual disease, this form of therapy focuses on disrupting the vascular environment so that dormant tumor cells do not gain the blood supply needed to grow (antiangiogenesis). 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 disease-free interval (DFI), or time before which the tumor recurred11. Specifically, the median DFI for dogs receiving metronomic had to be estimated because not enough dogs in this group had tumor recurrence, and the predicted median DFI was well over a year (410 days). Conversely, the median DFI was just 211 days for dogs that did not receive metronomic therapy following incompletely tumor excision. Interestingly, all dogs not receiving metronomic had tumor recurrence. Side effects associated with low dose chemotherapy are minimal and reversible, therefore it serves as a nice option for owners that want to pursue something that may have benefit and is not too intense on the patient.

August was started on metronomic therapy and a monitoring regimen of periodic physical examinations, blood work, and thoracic radiographs was instituted. She continues to tolerate therapy and thrive clinically, with no evidence of tumor recurrence at the 9-month mark. A total of one year of metronomic therapy is planned; thereafter simple monitoring will be continued. This case serves as an excellent example of how sometimes the most aggressive approach may not always be necessary or indicated for a particular patient, and that newer approaches such as those that combine more conservative surgery with metronomic therapy can serve as reasonable and potentially successful substitutes for more invasive interventions in older patients or those with concurrent diseases.

Submitted by:

Christine Mullin, VMD, Diplomate ACVIM (Oncology)

Hope Veterinary Specialists, Malvern

References

  1. McSporran KD. Histologic grade predicts recurrence for marginally excised canine subcutaneous soft tissue sarcomas. Vet Pathol 2009;46:928–933. http://vet.sagepub.com/content/46/5/928.long
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=Prognostic+factors+for+surgical+treatment+of+soft+tissue+sarcomas+in+dogs%3A+75+cases+(1986–1996).+J+Am+Vet+Med+Assoc+1997%3B211%3A+1147–1151.
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=Orthovoltage+radiation+and+weekly+low+dose+of+doxorubicin+for+the+treatment+of+incompletely+excised+soft-tissue+sarcomas+in+39+dogs
  1. Ettinger SN, Scase TJ, Oberthaler KT, et al: Association of argyrophi- lic nucleolar organizing regions, Ki-67, and proliferating cell nuclear antigen scores with histologic grade and survival in dogs with soft tissue sarcomas: 60 cases (1996–2002). J Am Vet Med Assoc 2006;228:1053–1062. https://www.ncbi.nlm.nih.gov/pubmed/?term=Association+of+argyrophi-+lic+nucleolar+organizing+regions%2C+Ki-67%2C+and+proliferating+cell+nuclear+antigen+scores+with+histologic+grade+and+survival+in+dogs+with+soft+tissue+sarcomas
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/10909459
  1. Forrest LJ, Chun R, Adams WM, et al. 
Postoperative Radiotherapy for Canine Soft Tissue Sarcoma. J Vet Intern Med 2000;14:578–582. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2000.tb02279.x/abstract;jsessionid=8C2427D3B93D9DD675C7F45539B7BAAD.f03t04
  1. McKnight JA, Mauldin GN, McEntee MC, et al. Radiation treatment for incompletely resected soft-tissue sarcomas in dogs. J Am Vet Med Assoc 2000;217:205-210. https://www.ncbi.nlm.nih.gov/pubmed/10909459
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=Marginal+Excision+of+Low-Grade+Spindle+Cell+Sarcoma+of+Canine+Extremities%3A+35+Dogs
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=Evaluation+of+primary+re-excision+after+recent+inadequate+resection+of+soft+tissue+sarcomas+in+dogs
  1. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=Second+intention+healing+after+wide+local+excision+of+soft+tissue+sarcomas+in+the+distal+aspects+of+the+limbs+in+dogs
  1. 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. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2011.0753.x/abstract

 

 

Posted in