Canine Cutaneous and Subcutaneous Soft Tissue Sarcoma: An Evidence-Based Review of Case Management
Canine cutaneous and subcutaneous soft tissue sarcomas (STS) account for 20.3% of malignant neoplasms of the skin. This article makes recommendations for the diagnosis, treatment, and follow-up in dogs with STS, using evidence-based medicine concepts. Although our review of the literature on the management of canine STS found many of the studies to be less than rigorous, board-certified specialists in internal medicine, surgery, pathology, oncology, and radiation oncology were able to make several recommendations based on the literature review: cytology and biopsy are important for presurgical planning; wide (>3 cm margins) surgical excision decreases the likelihood of tumor recurrence; the use of a histologic grading scale is useful in predicting biologic behavior; and, in select cases, chemotherapy and radiation therapy may be beneficial adjunct treatments to surgical excision. More research is necessary to determine minimum size of surgical margins, the impact of radiation therapy on incompletely resected tumors, the ideal chemotherapy protocol for high grade STS, and the optimal methods of monitoring dogs for tumor recurrence and metastasis.
Introduction
Canine cutaneous and subcutaneous soft tissue sarcomas (STS) arise from mesenchymal tissue, and they account for 4.5% of all neoplasms of the skin and 20.3% of malignant neoplasms of the skin.1 These tumors typically occur as solitary masses in middle-aged to older dogs. No breed or sex predilection has been reported. STS most commonly include: hemangiopericytoma (recently reclassified as perivascular wall tumors), fibrosarcoma, and peripheral nerve sheath tumors.2 Other sarcomas, such as hemangiosarcoma and histiocytic sarcoma, are technically sarcomas of soft tissue, but because their biologic behavior is more aggressive than the other tumors in this group and their cell of origin is hematopoietic, not mesenchymal, they are typically excluded from studies of STS. Classification of sarcomas often considered as STS is shown in Table 1. As a group, STS generally have a low rate of metastasis, have a pseudocapsule composed of compressed tumor cells, and require wide surgical margins for complete excision.
This article is the culmination of a series of discussions about a STS diagnosed in a golden retriever. Evidence available in the literature helped the owner (an epidemiologist, J.L.K.) and primary care veterinarian (A.S.) make a series of informed decisions about diagnosis and treatment that might not otherwise have been made. It is our hope that the information obtained in reaching these decisions will be helpful to other veterinarians.
“Evidence-based medicine is the consistent use of knowledge derived from biological, clinical, and epidemiologic research in the management of patients, with particular attention to the balance of benefits, risks, and costs of diagnostic tests, screening programs, and treatment regimens, taking account of each patient's circumstances, including baseline risk, comorbid conditions, culture, and personal preferences.”3 Evidence-based medicine (EBM) is a concept and term elaborated by a group of physicians, but the approach is equally applicable to veterinary medicine. EBM seeks to bridge the gap between research and patient care, resulting in effective patient management strategies. Practicing EBM requires identification of a clinical problem and developing a solution to that problem based on a critical review of the available scientific information. Currently, most decision making in veterinary medicine is based on expert opinion, anecdote, and experience. The proponents of EBM have classified the published scientific evidence based on its perceived quality of information. In general, the level of evidence in companion animal publications is low or very low.4 This manuscript will apply EBM principles to the management of cutaneous and subcutaneous STS in dogs.
The purpose of this publication, therefore, is to provide veterinarians with an evidence-based analysis of the literature related to the diagnosis, staging, surgical excision, histopathology, adjuvant cancer therapies, and follow-up for canine STS. This article is an application of the currently available data to make recommendations to improve clinical management and treatment outcome for dogs with STS and to indicate where gaps in knowledge exist.
Case Presentation
An 11 yr old spayed female golden retriever presented for evaluation of a cutaneous mass identified 1 wk previously by her owner. Upon examination, a 5 cm diameter firm, round subcutaneous mass was identified that appeared to adhere to the body wall of the left flank. The texture, reduced mobility, and rapid growth of the lump elicited concern for an abscess or a benign or malignant tumor. Fine-needle aspiration for cytology was performed, and the sample consisted predominantly of a population of pleomorphic spindle cells, suggesting a mesenchymal neoplasm, such as a perivascular wall tumor (hemangiopericytoma or myopericytoma), peripheral nerve sheath tumor, or fibrosarcoma.
Decision Making
One of the tenets of EBM is to ask clinically relevant questions and to use the available literature to answer them rather than using only prior experience or anecdote as the basis for answers. For this golden retriever, several clinically relevant questions about diagnosis and treatment were asked:
- 1.
What should be done preoperatively? In particular, who should perform the cytological evaluation of the aspirate? What additional staging tests should be performed?
- 2.
It was obvious that surgery would be required, but what should the qualifications of the surgeon be?
- 3.
Depending on the tumor type, wideness of histologic margins, and tumor grade indicated in the pathology report, would additional surgery, radiation therapy (RT), or chemotherapy be warranted? It this case, the golden retriever had a comorbid condition, recurrent pneumonia, which was anticipated to increase risk of complications from immunosuppressive chemotherapy or from the multiple anesthetic episodes required for RT.
- 4.
Finally, what should be the plan for monitoring the dog for tumor recurrence or metastasis based on the histopathological grade of the tumor?
Methods and Materials
Articles relevant to the clinical management of canine STS were identified by searching the literature published between January, 1998 and December, 2012 (A.E.H. and J.L.K.). The following steps were taken:
- 1.
Searching the scientific literature by means of PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) using the following tumor search terms: soft tissue sarcoma, fibrosarcoma, peripheral nerve sheath tumor, hemangiopericytoma, malignant schwannoma, neurofibrosarcoma, liposarcoma, myxosarcoma, malignant mesenchymoma, leiomyosarcoma, rhabdomyosarcoma, lymphangiosarcoma, undifferentiated sarcoma, malignant fibrous histiocytoma, and malignant spindle cell tumor.
- 2.
Reviewing the online table of contents from the following journals over this same time period to ensure no relevant articles were overlooked:
Journal of the American Veterinary Medical Association
Journal of the American Animal Hospital Association
Journal of Small Animal Practice
Journal of Veterinary Internal Medicine
Veterinary and Comparative Oncology
Veterinary Pathology
Veterinary Surgery
- 3.
Eliminating single case reports; review articles; articles not written in English; and diagnoses of histiocytic sarcoma, osteosarcoma, chondrosarcoma, synovial cell sarcoma, hemangiosarcoma, and melanoma (melanosarcoma). Publications not differentiating STS affecting the oral cavity, skeleton, or viscera from cutaneous or subcutaneous sarcomas were included only if the cutaneous or subcutaneous tumors comprised most of the cases. Publications including species other than the dog were included only if dogs comprised at least two-thirds of the cases. Publications reporting tests, procedures, and treatments not available to the general practice veterinarian or widely available on a referral basis were also excluded.
- 4.
Publications prior to 1998 were included if they were commonly cited in the selected references from 1998–2012.
The evidence from the selected papers was graded using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system for evaluation of studies used to develop clinical guidelines. GRADE takes into account the strength of the study design (retrospective case series, prospective case series, case-control study, cohort study, randomized controlled trial) and other important components of methodology.5 In the GRADE approach and most other systems, only randomized trials are given a grade of “high.” The grade and summary critique of each article are included in the appendix. Small sample size, lack of a comparison group, and non-representative cases were the most common problems with the reviewed studies. All articles were graded by a single author (J.L.K.) with expertise in study design and statistical methods. The appendix gives the grade assigned to each article and briefly summarizes the reasons for the assigned grade.
The graded reference list was provided to the authors and they were asked to analyze the relevant articles and make case management recommendations in their area of expertise based on evaluation of all the relevant articles and on the strength of the evidence.
In deciding about the overall strength of evidence regarding a given topic, some of the considerations that were taken into account were the consistency of the finding across studies, the magnitude of the effect, and whether all or most of the studies showing the effect were free of bias that could be responsible for the observed effect. Because no relevant randomized controlled trials were identified, these considerations assume particular importance in our review. The GRADE working group lists certain factors that increase one's belief in the validity of an association.5 Among the factors that increase one's confidence are (1) a strong association (i.e., relative risk >2.0 or <0.5) based on consistent evidence from two or more studies with no plausible confounders; (2) very strong evidence of an association (i.e., relative risk >5.0 or <0.2) with no major sources of bias; and (3) evidence of a dose–response relationship. Some factors that decrease one's belief in an association are also given in the GRADE approach; as mentioned above, these were taken into account in grading individual studies.
In subsequent sections, board-certified specialists in internal medicine, oncology, surgery, pathology, and radiation oncology discuss the literature supporting the decisions made in this case and generalize the information to other dogs with cutaneous or subcutaneous STS.
Results and Discussion
Evidence Regarding Preoperative Diagnostic Evaluation
- 1.
Use cytology performed at a reference laboratory for diagnosis and presurgical planning in dogs with cutaneous and subcutaneous masses since it is useful in a wide variety of tumors, including STS. If inflammation is reported, consider a preoperative biopsy, as cytology may produce a false negative result.
- 2.
Perform a needle core, wedge, or punch biopsy if aspiration cytology cannot confirm the diagnosis of a cutaneous mass.
- 3.
Aspirate or biopsy regional lymph nodes even if they are normal size. This recommendation is supported by only a few cases, but since aspiration is simple, inexpensive, and reasonably accurate, positive results may change treatment or prognosis.
The length of time a tumor is present before evaluation, the size of the tumor, and palpation are frequently cited by veterinarians as having predictive value for outcome. All studies addressing these issues were graded very low due to their retrospective design, failure to take into account likely confounding variables such as prior surgery, and the inability to generalize palpation criteria to a variety of different patients and veterinarians.6,7 In one study, the longer a tumor was present prior to resection, the greater the chances that tumor would recur after surgery.6 Tumor size was not a consistent predictor of outcome, with only one of three studies reporting that tumors >5 cm were more likely to be associated with an incomplete resection and consequently with a substantially greater risk of relapse than tumors <5 cm.8–10 Dogs with tumors described as invading underlying structures based on palpation had both a decreased disease-free interval and survival time.7
Following identification of a cutaneous or subcutaneous mass by palpation, clinical staging may involve cytology or preoperative biopsy to determine the likely presence of a tumor, radiographs and regional lymph node aspirates to investigate the possibility of metastatic disease, and blood tests to assess overall patient health. While these are nearly universally accepted components of presurgical evaluation, review of the literature found no evidence to support the use of routine blood tests or thoracic radiographs as staging tools in dogs with possible STS, but these tests are still considered standard of care and should be performed in dogs with suspected STS.
The literature review identified six articles, five graded very low and one low, evaluating the correlation of cytology with histology for various masses.11–16 Despite the low grade of evidence from individual studies, when the results of all six studies are considered, cytology shows good-to-excellent diagnostic accuracy for cutaneous and subcutaneous tumors. False negative results often stem from samples obtained by inexperienced veterinarians or hemangiopericytoma misdiagnosed as inflammation.13,16 Cytology samples from canine STS interpreted by referring veterinarians in-house appear to have a disproportionate number of false negative results.11 Since the consequences of diagnosing a STS as a benign lesion are serious, cytology samples from skin masses should be evaluated by a cytopathologist whenever possible.
In this golden retriever, the cytological diagnosis was mesenchymal tumor, which was consistent with the eventual histological diagnosis of hemangiopericytoma, and all further staging decisions were made based on the assumption that the biopsy would reveal a STS. Results of a fine-needle aspirate cytology without tumor cells may be useful since it makes the diagnosis of a readily exfoliating tumors, such as a mast cell tumor, much less likely. In a dog with a mass suspicious for, but not conclusively identified as, a tumor, an incisional biopsy should be recommended. Since cytology was consistent with a STS and wide excision was possible, a biopsy was not performed; however, for dogs with an extremity tumor requiring amputation to resect the tumor, a biopsy should be strongly recommended to confirm the diagnosis before proceeding with a radical surgery.
The literature review identified three articles, two graded very low and one graded low, addressing the utility of preoperative incisional biopsy for cutaneous and subcutaneous masses.8,15,17 The common types of preoperative biopsy, punch, wedge, or needle core, appear to have equal accuracy when compared to excisional biopsy, and for subcutaneous masses, needle core biopsy is very accurate.8,17 The determination of STS grade is an additional benefit of preoperative biopsy compared to cytology, although there is a moderate risk grade may be underestimated by a preoperative biopsy.8 If cytology shows sarcoma (or mesenchymal tumor) without a suggestion of the cell of origin, a biopsy is required to differentiate between a STS and other sarcomas, such as hemangiosarcoma or histiocytic sarcoma. Since tumor behavior and treatment are very different for these sarcoma types, the knowledge of the exact tumor types helps a veterinarian explain more precisely the treatment options and prognosis to the owner. The information should be conveyed to the owner with the caveat that preoperative biopsies can over- or underestimate grade. Thus, the ultimate diagnosis and treatment plan may change.8
When a STS occurs on the extremities, the regional lymph node (popliteal, superficial cervical, axillary, or inguinal) is commonly evaluated using aspiration cytology, incisional biopsy, or excisional biopsy as part of the clinical staging process. When STS occurs on the trunk, as in this dog, identification of the draining lymph node can be more challenging. The authors found no articles defining the anatomy of draining or sentinel lymph nodes in dogs with STS. Lymphadenopathy was not identified in this golden retriever.
We identified no studies specifically designed to evaluate the frequency or impact on prognosis of regional lymph node metastasis in dogs with STS. In studies where regional lymph node metastasis is described but is not the focus of the study, it appears to occur infrequently.6,11
In a study of sensitivity and specificity of aspiration cytology versus needle core lymph node biopsy, only a small number of STS cases were included, thus precluding a recommendation about which procedure is best in dogs with STS.18 Because metastatic tumor cells can be identified in normal-sized lymph nodes, even normal-sized regional lymph nodes should be evaluated for metastasis.18
Evidence-Based Recommendations for Excision of Soft Tissue Sarcoma
- 1.
Plan surgery to achieve complete excision to decrease the likelihood of recurrence and increase survival time.
- 2.
Wide excision (surgical margins > 3cm in all directions and one fascial plane deep to the tumor) is recommended to achieve a complete excision (histologic margins of > 3mm in all directions) for STS.
- 3.
Amputation may be required to achieve a complete excision for STS in an extremity.
- 4.
Surgery by a board certified surgeon may result in improved ability to achieve complete excision when compared to surgical residents, but studies of surgery performed by general practitioners have not been performed. More research is needed on this question.
- 5.
Consultation with a radiation oncologist is warranted if the tumor cannot be completely resected.
One of the primary principles of surgical oncology is complete mass excision. This certainly holds true for the soft tissue sarcomas, whose biologic behavior tends to be locally invasive with low metastatic potential. At present, the clinical recommendation for STS is wide excision. A wide excision is defined as surgical margins extending greater than 3 cm in all directions from the tumor, and one fascial plane deep to the tumor.19 In cases of tumors on limbs, radical surgery (i.e., amputation) may be indicated. Unfortunately, the evidence regarding surgical recommendations is mostly anecdotal and has low or very low scientific evidence, primarily due to low case numbers within study groups and lack of statistical power and a comparison group. In addition, most of the studies cannot be compared to one another since methodologies and criteria for inclusion differ greatly.
A review article and numerous studies, graded very low or low, have evaluated width and completeness of excision and how they relate to tumor recurrence and survival times. These studies have examined the degree of resection and found that a wide excision decreases the likelihood of local recurrence and extends survival times.6,9,16,20–26 Despite the low level of evidence from individual studies, the fact that multiple studies report the same result leads to the conclusion that complete excision is a critical determinant of recurrence and survival time. When resection is not complete, revision of the prior surgical scar can also reduce the likelihood of recurrence as well as improve survival in cases with close or incomplete margins.11,24 In dogs with recurrent STS, tumors tend to recur 1–3 yr after surgery and median time to recurrence is approximately 1 yr.11,22,24 However, some reports have stated that a marginal excision is just as successful as a wide excision, especially if the STS is low-grade (1 or 2), if postoperative RT is used, or in tumors at or distal to the elbow joint .27–30 Again, caution should be exercised when comparing study results since methodologies and study populations vary widely.
Wide excision of STS requires an intimate knowledge of local anatomy. It would make sense, therefore, that surgical specialty training would allow a wider excision with improved outcomes. There are few papers related to the subject of surgical specialty training and completeness of excision, with mixed results. Monteiro et al. found an advantage in completeness of surgical excision when tumors were removed by board certified surgeons compared to surgical residents.20 This study should not be over interpreted because the level of evidence was graded as very low and it did not address the role of veterinarians without surgical specialty training in the surgical management of STS. Demetriou et al. analyzed factors potentially impacting the outcome of STS treatment, including the type of veterinarian performing surgery: surgical specialist or general practitioner.27 Because the study did not include any cases with completely excised tumors and because of statistical issues, no conclusions can be drawn from this study about qualifications of the surgeon for optimal surgical resection of STS. Although much more research is needed in this area, the need for complete resection with wide surgical margins suggests that surgeons with experience and advanced training in oncologic surgery might have an advantage in obtaining the desired resections.
In this golden retriever, in whom the tumor was excised by an experienced board-certified surgeon (M.P.), the location of the tumor on the flank with loose skin allowed 3 cm wide surgical margins resulting in histopathologic margins free of tumor cells by 3–11 mm. Because the surgical margins of 3 cm resulted in a minimum of 3 mm margins on all borders of the excision, no further surgical treatment was deemed necessary.
Evidence Regarding Histopathology Submission and Interpretation
Histopathology plays an important role in the definitive diagnosis of STS and provides important prognostic information to help guide treatment of these patients. Interpreting the veterinary pathology literature on canine STS is difficult because of various inconsistencies, such as which neoplasms are included in the category of STS, the definitions of complete or incomplete excision, the level of mitotic index (MI) conferring prognostic significance, and tumor grade. Nevertheless, histologic subtype of STS, MI and histologic tumor grade, and completeness of surgical margins are important components of the biopsy report that can be used in guiding clinical decisions and indicating prognosis. Reports lacking any of these components should prompt a conversation with the pathologist. Appropriate biopsy sample preparation and submission can help yield the most useful pathology report possible.
Guidelines for excisional biopsy submission for probable STS:
- 1.
Submit entire tumor to pathology laboratory.
- a.
Preserves overall tumor architecture by including overlying skin if present and by making partial thickness incisions into large tumors rather than completely transecting, which would alter the orientation of the tumor and affect margin evaluation.
- b.
Allows assessment of necrosis throughout the tumor, which is a component of grading scheme.
- 2.
Surgical margins.
- a.
Become familiar with your laboratory's protocols for margin assessment.
- b.
Ink or mark, with suture, specific margin of interest to ensure histologic evaluation.
- 3.
Communication.
- a.
Indicate clinical impression of completeness of excision on biopsy request.
- b.
Contact the pathologist if MI, histologic grade, or margin assessment is not included in the biopsy report.
- c.
Contact the pathologist and/or an oncologist when more malignant tumors are suspected such as amelanotic melanoma or histiocytic sarcoma.
- d.
Contact the pathologist and/or an oncologist for guidance when immunohistochemistry (IHC) is recommended.
Histologic Subtype of STS
The literature review identified six articles, all graded low or very low, addressing the effect of histologic subtype of STS on prognosis.9,16,22,25,31,32 Most studies indicate that the biologic behavior of the various subtypes is similar, supporting the grouping of these tumors. Some reports suggest that perivascular wall tumors (including hemangiopericytomas) and peripheral nerve sheath tumors have a less aggressive biologic behavior and are more likely to be lower grade than other STS; however, pathologists vary in their criteria for distinguishing between perivascular wall tumors and peripheral nerve sheath tumors.23,25,31
IHC is a tool recommended by pathologists to aid in determination of cell or tissue type of origin, particularly to help rule out other types of sarcoma with a worse prognosis and more aggressive biologic behavior, such as histiocytic sarcoma or amelanotic melanoma. Guidance from the pathologist and an oncologist may be helpful in determining the utility of IHC in a given situation.
Mitotic Index and Tumor Grade
For canine STS, the widely used histologic grading scheme (with grades of 1, 2, and 3; Figures 1A–C) includes three main features: MI, tumor differentiation, and necrosis. Increasing tumor grade is the result of a combination of increased MI, which is the number of mitoses in 10 high power (400x) fields; decreased degree of tumor differentiation, which reflects how closely the cells and growth pattern resemble the tissue type of origin; and increased percentage of necrosis within the neoplasm (categorized as lack of necrosis, necrosis encompassing <50% of the mass volume, or necrosis occupying >50% of the mass volume). Grade may be under- or overestimated if only portions of the tumor are submitted for histopathology. A grade 1 STS is typically well-differentiated with a low MI and without necrosis (Figure 1A), although one of these categories can be more intermediate and remain a grade 1 tumor. A grade 2 STS typically has a combination of either a more intermediate degree of differentiation, moderately increased MI, and/or the presence of necrosis (Figure 1B). A grade 3 STS typically is somewhat poorly differentiated with an increased MI and the presence of necrosis (Figure 1C).
Citation: Journal of the American Animal Hospital Association 52, 2; 10.5326/JAAHA-MS-6305
The literature review identified four articles, all graded low or very low, evaluating the effect of histologic grade or MI on prognosis.22,23,31,32 The evidence suggests that tumor grade is more predictive than MI alone. Despite the low level of evidence from individual studies, when the results of all studies are considered together, tumor grade has good prognostic value. Increasing histologic grade predicts tumor recurrence following marginal excision and is more predictive than MI alone; it should be kept in mind, however, that the histologic definition of marginal excision, also referred to as close surgical margins, varies among studies.23,25 Histologic grade is directly related to tumor recurrence and may be predictive of metastasis.22,23,32 Reports vary as to whether histologic grade predicts survival.21,22 One study subdivided marginally excised STS by tumor grade and found the percentage of local recurrence during a minimum follow up of 24 mo to be 7% for grade 1, 34% for grade 2, and 75% for grade 3 tumors.23 MI alone may have some prognostic value, including prediction of tumor recurrence, metastasis, and survival time, although the studies vary as to the MI cut-off value that is considered predictive, making comparison of these studies difficult.22,23,31,32
Surgical Margins
Each histopathology laboratory follows different protocols for gross and histologic assessment of surgical margins. Familiarity with the standard operating procedure is important for an understanding of the surgical margins provided in the biopsy report. There is variation in the literature in the definition of a clean or complete surgical margin as compared to a close or marginal excision. A marginal excision is typically considered to be any histologic margin <3 mm (Figure 1D). Incomplete margins are typically defined as the presence of neoplastic cells at one or more surgical margins (Figure 1E).
As discussed above, completeness of surgical margins has good prognostic value for STS. Incomplete surgical margins are a risk factor for local recurrence and shorter disease-free interval.7,16,24 Complete surgical margins predict a lack of tumor recurrence locally and increased tumor-free survival time.22,23
In the current case, the biopsy was consistent with a hemangiopericytoma, a type of perivascular wall tumor, with well-differentiated morphology, a low MI of 1 per 10 high power fields, and no observed necrosis. Based on these criteria, this was consistent with a grade 1 STS, and the histologic margins were complete (margins free of tumor cells by 3 to 11 mm).
Evidence Regarding the Recommendation for Adjuvant Chemotherapy
Very few veterinary studies have evaluated the efficacy of chemotherapy for STS, and all of the reports were graded as providing a very low to low level of evidence because of small sample size, frequent retrospective study design, and lack of a comparison group. Much of the clinical approach in dogs is based on human oncologic practice, in which chemotherapy for these tumors also remains controversial. Nevertheless, a recently updated meta-analysis of 18 human studies found that adjuvant doxorubicin, with or without ifosfamide, provided modest benefits in local tumor control, metastatic control, and overall survival amongst nearly 2,000 patients with localized resectable STS of all grades.33
A retrospective study of 39 dogs with high-grade axial, appendicular, and visceral STS found that dogs receiving post-surgical doxorubicin treatment did not experience benefit in disease-free interval (both in terms of time to local tumor recurrence and time to metastasis) or overall survival compared to dogs that did not receive chemotherapy.34 As this was not a randomized trial, the authors acknowledged the potential for selection bias as to which dogs received doxorubicin treatment. The lack of improvement with chemotherapy in dogs with high-grade tumors dampens enthusiasm for the use of systemic chemotherapy in low- to intermediate-grade tumors that typically have lower proliferation rates and would therefore be expected to be less susceptible to chemotherapy in addition to having lower rates of metastasis.
In another small study, the combination of ifosfamide with doxorubicin was well tolerated in dogs with hemangiosarcoma or STS arising from the skin and adnexae. However, due to the small number of dogs with cutaneous tumors (N = 12) and considerable variation in treatment protocols, efficacy could not be assessed specifically in the dogs with cutaneous tumors.35
Local administration of chemotherapy was investigated as an alternative to RT to enhance tumor control after marginal surgery (surgery excising visible tumor without removing all microscopic disease) in two small, uncontrolled prospective studies. In the first study, tumor-free survival in six dogs that received weekly intralesional 5-fluorouracil injections around the surgical incision site was 100 and 83% at 1 and 2 yr, respectively.36 The treatments were well tolerated. In contrast, intraoperative placement of a cisplatin-impregnated biodegradable implant within the tumor bed was associated with unacceptable wound healing complications.37 Local recurrence was 16.6% over a median follow-up time of 2.4 yr. Since neither of these studies had a comparison group, it is difficult to assess impact of local chemotherapy on tumor control, particularly since the surgical techniques, histologic margin analysis, and the presence of residue tumor after surgery were not reported.
Although still largely considered investigational, metronomic chemotherapy (daily, low-dose oral chemotherapy) is gaining acceptance as an alternative medical therapy for both local and systemic tumor control. Rather than outright killing neoplastic cells, metronomic chemotherapy works through antiangiogenic and immunomodulatory mechanisms. A retrospective study of 85 dogs with incompletely resected STS (all visible tumor removed at surgery but neoplastic cells extended to the surgical margins histologically) reported that median time to tumor recurrence was nearly doubled in dogs that received low-dose cyclophosphamide daily in combination with a nonsteroidal anti-inflammatory drug compared to those that received no further treatment (410+ versus 210 days, respectively).38 Another study, evaluating daily chlorambucil treatments in dogs with measurable tumors, included nine dogs with STS.39 One dog experienced complete clinical resolution of the tumor for greater than 17 wk and three more dogs maintained stable disease for at least 7 wk.39 These encouraging preliminary results warrant further investigation through prospective, randomized trials.
In the case presented here, chemotherapy was not indicated. The wide surgical margins were expected to provide effective local control. The low metastatic potential of this grade 1 tumor rendered systemic therapy unwarranted.
- 1.
Chemotherapy is not warranted for completely resected Grade 1 or 2 STS.
- 2.
Because of their high rate of metastasis, chemotherapy should be considered in dogs with Grade 3 STS, but evidence to support its efficacy is limited. Consultation with an oncologist will help to determine current standard of care.
- 3.
Metronomic chemotherapy should be considered for dogs with incompletely resected tumors if further surgery and/or RT is not possible.
Evidence Regarding RT Recommendations
Radiation oncologists may be asked to discuss RT with owners of dogs with incompletely excised STS or STS that cannot be surgically removed because of their size or location.
The current approaches to RT for dogs with incompletely resected STS are based in part on standard of care in humans with STS, although optimal radiotherapy management of humans has not been completely defined. An analysis and synthesis of data from 39 human studies including over 3500 patients showed that RT improved the local control in patients following surgery.40 However, several different types of RT were administered and varying treatment protocols were used in these patients, a situation similar to the state of treatment of STS in veterinary patients.
All RT studies identified in this literature search were graded very low because of small sample size, retrospective design, and lack of a comparison group. Treatment protocols were highly variable in terms of total dose, fraction size, and treatment intervals. In one study the type of radiation used was not reported.28 All the other studies reported using megavoltage radiation, with either a cobalt −60 teletherapy unit or a 4 or 6 MV linear accelerator, for treatment.
Postoperative RT Following Incomplete Excision
In three studies of dogs with STS undergoing RT following incomplete excision, the dogs were treated with a total of 42–63 gray (GY) divided into 10 to 21 fractions of 3 to 4.5 GY each.4,28,29 Despite somewhat different study populations, median time to tumor recurrence (approximately 2 yr following treatment) was similar in two larger studies.28,29 Median survival was reported in one study, calculated as 5.1 yr.28 Because of lack of adequate comparison groups, it is not known what survival times and time to tumor recurrence would have been expected without RT.
In another study, a total of 32–36 GY were administered in four 8–9 GY fractions over 21 days following intentional incomplete tumor excision.27 Local tumor recurrence was 35% at 3 yr. Although this outcome is similar to those in one study of dogs treated with 10–19 fractions of RT, no study has been performed directly comparing these two forms of RT or comparing three or four fractions of RT to incomplete excision alone.9,28
RT for Non-Resectable Tumors
The use of three to four 8 GY fractions totaling 24–32 GY of RT for the treatment of non-resectable STS has been described in two studies.41,42 In some dogs, tumors decreased in size and in others growth stabilized for approximately 5–9 mo. These results are difficult to interpret because the growth rate and behavior of untreated STS has not been adequately described. Median survival times for treated dogs were slightly less than 1 yr.
The golden retriever of this report had a low grade tumor that was completely excised; consequently, she was not evaluated for RT.
- 1.
In dogs with STS that are incompletely resected or non-resectable, consultation with a board-certified radiation oncologist should be considered.
- 2.
Prolonged time to tumor recurrence and survival time are reported following RT protocols using multiple different radiation doses, the dose per treatment, and number of treatments. Data should be cautiously interpreted because of the lack of comparison groups in all the studies. A board-certified radiation oncologist will suggest the appropriate treatment protocol for an individual patient.
Evidence Regarding Postoperative Follow-Up
No study addressed the optimal length and frequency of follow-up after treatment of a STS. Some information can be gleaned from studies primarily addressing other topics such as outcomes following surgery and RT. Several studies report follow up times of greater than two yr.6,11,22,31 The median time to recurrence in two studies was approximately 1 yr, but extremely late recurrences 3–5 yr following diagnosis were also reported.6,22,31 In the absence of specific evidence, a reasonable plan would be evaluation by a veterinarian quarterly with more frequent at home monitoring by the owner for the duration of the dog's life.
Following surgery, the owner and primary care veterinarian drew a “body map” of all palpable masses, and the skin of this golden retriever was palpated twice a mo by the owner to detect any new cutaneous or subcutaneous masses as well as recurrence of a mass at the original surgery site. The primary care veterinarian also palpated the surgery site, lymph nodes, and skin to detect STS recurrence, metastasis from the original STS, or development of a new STS. A fine-needle aspirate was obtained from any new mass. Cytologic samples were sent for evaluation by a cytopathologist, without identification of tumor recurrence or a second malignancy. During these examinations, thoracic radiographs were obtained without identification of tumor recurrence or metastasis. The literature review identified no recommendations for additional monitoring tests, beyond thoracic radiography and physical examination. This golden retriever was euthanized 11 mo after removal of the STS because of a metastatic pancreatic adenocarcinoma.
Conclusion
Randomized controlled clinical trials provide the highest level of evidence to support clinical decisions. According to the GRADE system, the available evidence regarding the management of canine subcutaneous and cutaneous STS does not surpass the low or very low level. Although no relevant randomized controlled clinical trials were identified during the literature search, based on the analysis of the information presented here we can make some tentative recommendations for certain diagnostic and therapeutic interventions.
Results of aspiration cytology of skin masses show good correlation with ultimate histological diagnosis, making it a useful preoperative test to facilitate preoperative planning since surgery is the mainstay of treatment for STS.
Insufficiently wide surgical margins were frequently and repeatedly identified as an important predictor of tumor recurrence and shorter survival time. Thus, we can recommend aspiration cytology of a cutaneous mass as a method of identifying the likely presence of a STS and, subsequently, the need for wide surgical margins or even radical surgery, such as amputation, in some cases of extremity STS.
Histological grade was another important predictor of tumor recurrence, metastasis, and survival. If the biopsy report does not contain an assessment of both adequacy of surgical margins and tumor grade, the pathologist should be contacted to obtain this information because additional treatment may be warranted in dogs with unfavorable prognostic factors.
Finally, despite a complete lack of evidence supporting this, common sense dictates that dog owners should be encouraged to monitor and report new skin masses and general practitioners should diagram, measure, and record the size and location of all skin masses, as well as the results of aspiration cytology, in order to identify the development of new, recurrent, or metastatic tumors as early as possible. If new, recurrent, or metastatic tumors are identified, regional lymph nodes should be identified and aspirated as well. Such monitoring has the additional advantage of sometimes identifying other tumors as well.
EBM directs current therapy and also future avenues of clinical investigation. This review identified several areas where research is lacking on important clinical questions with regard to the management of STS, most critically, in designing studies of sufficient size and with appropriate comparison groups. The questions listed are those we consider to be of highest priority.
What is the biologic behavior of incompletely resected STS which are monitored, but not treated with adjuvant therapy?
Given that the adequacy of the resection and the grading of the tumor influence the development of recurrence and metastasis, does the level of training of the pathologist or the surgeon influence these outcomes?
What is the minimal width of a surgical margin for dogs with STS to prevent local recurrence?
Can tumor recurrence or metastasis outcome be better predicted by the routine use of IHC markers?
For dogs with incompletely resected STS, which follow-up adjuvant treatment results in the best outcome, scar revision, or RT? Does this depend on factors such as site and grade?
What are the optimal chemotherapy and RT protocols for dogs with incompletely resected or grade 3 STS?
How, how often, for how long, and by whom should dogs be monitored for recurrence or metastasis of STS?
(A) Grade 1 perivascular wall tumor (hemangiopericytoma). Grade 1 soft tissue sarcoma (STS) designation since neoplasm is well-differentiated with low mitotic index (MI) and lack of necrosis. Hematoxylin and eosin (H&E) stain. 20x objective. (B) Grade 2 STS. Grade 2 designation since neoplasm has moderate differentiation, low MI, and small areas of necrosis (necrosis and hemorrhage at top left of image, denoted by *). H&E stain. 20x objective. (C) Grade 3 STS. Grade 3 designation since neoplasm is poorly differentiated with a high MI (note the 4 mitotic figures, each to the right of an *), and with areas of necrosis (not pictured). H&E stain. 40x objective. (D). STS with marginal excision. Neoplastic cells (left) are 1 mm from inked surgical margin (yellow-brown ink at right, black arrows). H&E stain. 4x objective. (E) STS with incomplete excision. Neoplastic cells present at the inked surgical margin (pink-magenta ink at right of image, denoted by *). H&E stain. 20x objective. H&E, hematoxylin and eosin; MI, mitotic index; STS, soft tissue sarcoma(s).
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