Introduction
Mast cell tumors (MCTs) and soft tissue sarcomas (STSs) are the most common cutaneous and subcutaneous malignancies affecting dogs.1,2 The vast majority of MCTs and STSs are solitary tumors and they can occur anywhere on the body.2 The biological behavior of both tumor types varies from well-differentiated tumors, which can present as slow growing solitary masses, to poorly differentiated tumors, which are frequently rapidly-growing and metastasize.3
Tumor histologic grade can be used to prognosticate and plan treatments. For MCTs, there are 2 widely recognized histological grading systems: the 3-tier Patnaik classification of well, intermediately, and poorly differentiated (grade I, II and III) and the 2-tier Kiupel classification of low or high grade.4,5 For STSs, a 3-tier histological grading system is widely used and consists of low, intermediate, or high grade (or grade I, II or III).6 Histological grade classifications have been used in combination with proliferation markers such as mitotic index and Ki67 index to try to predict biological behavior and prognosticate.3–5 For both tumor types, a higher histological grade, higher mitotic index, and higher Ki67 index have been shown to be correlated with shorter median survival times.5–8
Complete surgical excision is the treatment of choice for both tumor types to achieve optimal local control. Both MCTs and STSs exhibit characteristic microscopic extension of tumor cells beyond the main tumor bed and, as such, to achieve complete surgical resection, grossly visible tumors are removed with a relatively wide margin of grossly normal surrounding tissue.9 The optimal planned surgical margins for each tumor type remains controversial. For MCT and STS, historically, surgical margins of 2-3 cm lateral and at least 1 fascial plane deep to the gross tumor have been recommended.10,11 More recently, it has been documented that the vast majority of grade 1 and 2 cutaneous MCTs will be completely excised when resected with a 2-cm lateral margin and 1 deep fascial plane.12 A modified proportional margins approach has also been documented for MCTs.13,14 Regardless of specific curative-intent surgical margins approach, a considerable proportion of MCTs and STSs are not suitable candidates for curative-intent surgical excision, typically due to a combination of their size, lack of available surrounding tissue (eg, distal limb), and patient or owner factors. In such cases, intentional marginal excision followed by adjuvant therapy may be selected as an optimal approach.
Marginal excision is a surgical margin concept derived from human musculoskeletal sarcoma surgery and is defined as removing the lesion en-bloc with the plane of dissection through the pseudocapsule or reactive tissue surrounding the lesion, leaving microscopic disease at the margin of the wound in a high percentage of cases.15 When a purposeful marginal excision of MCT or STS is planned, adjuvant radiation therapy has been shown to be effective for local control and is generally commenced as soon as wound healing is achieved.16,17 Therefore, fast uncomplicated healing of the surgical wound is advantageous for early institution of adjuvant radiation therapy.
Rapid surgical wound healing without complications is desirable to avoid unnecessary patient morbidity and increased treatment costs associated with wound healing complications. Some authors have suggested that wound healing following MCT excision could be impaired.18 Mast cells contain cytoplasmic granules that store inflammatory mediators like histamine, proteases, and cytokines. Preoperative tumor manipulation (eg, palpation or surgical skin preparation) or surgical trauma may precipitate degranulation and the extracellular release of these mediators. The release of these mediators is the rationale for concern about MCT surgical wound healing. An in vitro study19 showed that histamine inhibited epithelial outgrowth dose dependently, and a study20 in mice demonstrated that histamine- induced suppressor macrophages inhibited both fibroblast growth and wound healing. However, a previous questionnaire-based study21 in dogs found that incompletely excised cutaneous MCTs had wound healing complications similar to those of completely excised cutaneous histiocytomas, calling into question the clinical importance of the aforementioned biologically active substances in canine MCT surgery patients.
The main objective of our study was to evaluate surgical wound healing after intentional marginal excision of cutaneous MCT and subcutaneous STS in dogs and compare the outcomes. We hypothesized that there would be no difference in wound healing times and complication rates between dogs with marginally excised MCTs and dogs with marginally excised STSs. The secondary goal was to identify potential risk factors for wound healing complications after intentional marginal excision of MCTs and STSs in dogs.
Materials and Methods
Case selection
Medical records of all dogs that underwent an intentional marginal excision of a de novo cutaneous MCT or subcutaneous STS from October 2008 to December 2015 were reviewed. Dogs were enrolled in the study if they had no history of concurrent disease (endocrinopathy or neutropenia), administration of glucocorticoids, hormonal or chemotherapeutic drugs, or neoadjuvant radiotherapy and complete follow-up information was available. Patients were included when primary wound closure was performed by direct apposition of the wound edges or when the wound was reconstructed during the same surgery using a subdermal plexus flap. Patients were excluded if the wound was closed with an axial pattern flap. Data retrieved from the medical records for all dogs in both groups included breed, sex, age, body weight, tumor location, tumor size, clinical stage, wound closure method, 3-tier histologic grade, histological margin assessment, time to complete wound healing, presence and type of wound healing complications (referral institution and primary care medical records).
Time to complete wound healing was defined as a period of time in days from the day of surgery until the day of skin suture removal or until the day of complete epithelialization of wounds that healed by second intention. Wound healing complications were classified based on their severity as minor (further surgical intervention not required) or major (requiring further surgical intervention or anesthesia). Reported histological margins were used to classify excisions as complete if there was > 2 mm of normal tissue between the tumor and the inked edges in all directions, complete but close if tumor cells extended to ≤ 2 mm of the inked edges in ≥ 1 section or if the histopathologist commented that the margins were very close in ≥ 1 section, and incomplete if tumor cells extended to the inked edges in ≥ 1 section.
Surgical procedures
All surgical procedures were carried out by a diplomate of the European College of Veterinary Surgeons (ECVS) or ECVS resident supervised by an ECVS Diplomate. Clinical staging was performed prior to surgery and consisted of cytology of fine-needle aspirates from the regional lymph node and abdominal ultrasound in the MCT group and 3-view thoracic radiography of the thorax in the STS group. In all dogs, the anesthetic protocol consisted of premedication with a combination of acepromazine (0.01 to 0.02 mg/kg, IM) and methadone (0.1 to 0.3 mg/kg, IM); propofol (2 to 4 mg/kg, IV) for induction and isoflurane for maintenance of general anesthesia. Cefuroxime (20 mg/kg, IV) was administered operatively 30 minutes prior to surgery, every 120 minutes peri-operatively and was discontinued at the end of surgery. Additionally, all dogs in the MCT group were administered intravenous chlorpheniramine maleate (4 mg/dog, IM) prior to surgery. In all dogs in both groups, subcutaneous tissues were approximated using poliglecaprone 25 suture in interrupted or simple continuous pattern; skin apposition was achieved using nylon suture in a simple interrupted or cruciate pattern. Surgical oncological principles were adhered to and where local subdermal plexus flap closure was deemed necessary gloves and kit were changed between tumor resection and flap reconstruction. Standard flap development and tension-relieving wound closure surgical principles were adhered to.
Statistical analysis
Baseline demographics including age, weight, sex, tumor location, tumor size, and the use of a subdermal plexus flap for wound closure were compared between the 2 tumor groups. Continuous data were assessed for normality using a normal quantile plot and the Shapiro-Wilk test; 2-sample t tests were used to compare normally distributed data, or data that were normally distributed after logarithmic transformation. The Kruskall-Wallis test was used for nonparametric continuous data, and categorical data were assessed with the Fisher exact and χ2 tests. The χ2 test was used to test for an association between the use of a subdermal plexus flap and the development of wound healing complications. The 2-sample Wilcoxon rank sum test was used to test for an association between the use of a subdermal plexus flap and time to complete healing. A P value < 0.05 was considered significant. All statistical analyses were performed using a commercial statistical software package (Stata version 13.1; StataCorp).
Results
The MCT group consisted of 77 tumors from 77 dogs. Represented breeds included: Labrador Retriever (n = 24), mixed breed (10), Golden Retriever (6), Staffordshire Bull Terrier (5), Boxer (5), Bichon Frise (2), Jack Russell Terrier (2), Beagle (2), Pug (2), and 1 each of 19 additional breeds. Thirty-nine dogs were female (33 neutered) and 38 were male (33 neutered). Mean ± SD age at the time of surgery was 8.2 ± 3.0 years (range 1.2 to 14.3 years) and mean ± SD body weight was 21.6 ± 11.0 kg.
Tumors occurred in the following locations: 25 (32%) pelvic limb, 21 (27%) thoracic limb, 14 (18%) head, 12 (16%) trunk, and 5 (7%) perineum. Mean ± SD tumor diameter was 28.8 ± 18.5 mm (range 5 to 110 mm). Frequency distribution of tumor Patnaik grades was as follows: 65 (84%) grade II, 7 (9%) grade III, and 5 (7%) grade I. Histopathology confirmed incomplete excision for 68 (88%) tumors, complete but close excision for 9 (12%) tumors and no tumors were completely excised. Overall, wound healing complications occurred in 22 (29%) of 77 cases. There were 22 minor complications and no major complications. Minor complications included partial wound dehiscence and subsequent second intention healing (8/22); partial wound dehiscence associated with suspected surgical site infection (SSI) and subsequent second intention healing (4/22); seroma (3/22); suspected SSI (3/22); bleeding (1/22); major wound dehiscence due to self-trauma with Elizabethan collar and second intention healing (1/22); serosanguineous discharge (1/22) and bruising (1/22). In 63 (82%) dogs, direct apposition of skin edges was achieved without a need for skin flap reconstruction. Fifteen of those 63 dogs (24%) experienced minor wound healing complications. Skin reconstruction with a local subdermal plexus skin flap was performed in 14 (18%) cases. The types of subdermal plexus flaps used included advancement (6/14); transposition (6/14); rotational (1/14) and bipediculated (1/14). Seven (50%) of these cases developed wound healing complications, all of which were classified as minor complications. In the MCT group, mean ± SD time to complete wound healing was 16.5 ± 7.5 days (range 10 to 59 days).
In the STS group, there were 49 tumors from 49 dogs. Represented breeds included: mixed breed (n = 8), Staffordshire Bull Terrier (5), Cocker Spaniel (5), Boxer (4), Lurcher (3), Golden Retriever (2), German Shepherd Dog (2), Hungarian Vizsla (2), West Highland White Terrier (2), and 1 each of 16 additional breeds. Twenty-seven dogs were female (25 neutered) and 22 were male (19 neutered). Mean ± SD age was 8.9 ± 2.4 years and mean ± SD body weight was 21.7 ± 13.1 kg. Tumors occurred in the following locations: 25 (51%) in the thoracic limb, 11 (23%) in the pelvic limb, 5 (10%) in the head, 5 (10%) in the trunk, and 3 (6%) in the perineum. Mean ± SD tumor diameter was 33.2 ± 25 mm (range 5 to 140 mm). Frequency distribution of tumor grades was as follows: 28 (57%) low grade, 14 (29%) intermediate grade, and 7 (14%) high grade. Histopathology confirmed incomplete excision for 44 tumors, complete but close excision for 5 tumors and no tumors were completely excised. Overall, wound complications occurred in 15 out of 49 cases (31%). There were 14 (29%) minor complications that included partial wound dehiscence and subsequent second intention healing (4/14); swelling and bruising (3/14), bruising (3/14); seroma (2/14), suspected SSI (1/14) and partial wound dehiscence, and suspected SSI with second intention healing (1/14). There was 1 major complication: a seroma with surgery required to place close suction drain, suspected SSI, partial dehiscence, and second intention healing. In 41 (84%) cases, direct apposition of skin edges was achieved without a need for skin reconstruction. Ten of these 41 (24%) dogs experienced minor wound healing complications. Skin reconstruction with a local subdermal plexus flap was performed in 8 (16%) cases. The types of subdermal plexus flaps used included advancement (3/8), transposition (3/8) and rotational (2/8). Five (63%) of these cases developed wound healing complications: 4 dogs had minor complications and 1 dog had a major wound healing complication. In the STS group, mean ± SD time to complete wound healing was 17.7 ± 9.3 days (range 9 to 61 days).
Data analysis
The MCT and STS groups did not differ in age, body weight, gender distribution, tumor size, tumor location, and proportion of dogs undergoing wound reconstruction with a subdermal plexus flap (Supplementary Table S1). No significant difference was found between the 2 groups with respect to time to complete healing (P = 0.66) and complication rate (P = 0.806) on univariate analysis. For both tumor types, wound reconstruction with a subdermal flap was significantly associated with longer time to complete healing (P < 0.01), with a mean of 22.2 ± 11.9 days for wounds that were reconstructed and 15.9 ± 6.7 days for those closed by direct apposition. Wound reconstruction with a subdermal plexus flap was also associated with a higher rate of complications (P = 0.004), with a complication rate of 55% (12/22) for reconstructed wounds and 24% (25/104) for directly apposed wounds.
Discussion
No difference in wound healing times or complication rates was detected between dogs that underwent intentional marginal excision of MCTs and those that underwent intentional marginal excision of STSs. The only significant risk factor found for wound healing complications and delayed wound healing was the use of a subdermal plexus flap for closure.
The previously demonstrated in vitro inhibitory effect of mast cell inflammatory mediators on cells involved in tissue healing18–20 was not appreciated via a clinical effect in this study. This finding was perhaps not surprising when the complex role of mast cells in wound healing in vivo is considered. Mast cells are important not only in pathological dysregulation but also in skin repair. They have been described as a “homeostatic orchestrator of skin healing” given that activated mast cells contribute and command important phases of healing including the inflammatory, proliferative, and reparative phases.22 Even in the higher grade MCTs, where we may expect increased concentrations or release of histamine, no association was found with a longer healing time or more wound healing complications, compared with dogs undergoing marginal resection of STS. The authors acknowledge that the numbers of patients with high grade MCTs in the study was low, making these findings more prone to type II error. Despite the intent for marginal resection, mast cells were found extending to at least 1 cut plane in the majority of patients suggesting that residual neoplastic mast cells could be expected within the wound bed. However, this is an assumption and the only way to be sure of this would be to take wound bed biopsies, which was not performed in these clinical patients.
The findings of the present study support the findings of Killick et al,21 who compared wound healing after MCT excision to wound healing following cutaneous histiocytoma excision. A peritumoral inflammatory response can often be seen in both MCTs and histiocytomas and this may have influenced healing in both groups. Soft tissue sarcoma was chosen as a comparative group in the present study because MCTs and STSs share characteristic microscopic extension of tumor cells beyond the main tumor bed, but STSs are not typically associated with peritumoral inflammation.23 Furthermore, the authors are not aware of reports of sarcoma cells having an impact on the normal process of tissue reparation.
Previously documented factors associated with MCT wound healing complications include tumor volume and a “baggy” appearance.21 In the present study, tumor size was not found to be associated with time to complete healing or wound healing complications. This could be explained by the relatively small size of the MCTs, the mean diameter of which was 28.8 mm. Also, the size was recorded as a measurement of mass diameter rather than mass volume so it is possible that if volume was considered, findings may have differed. Due to the subjective nature of a “baggy appearance” and possible association with subcutaneous rather than cutaneous MCTs, tumor appearance was not evaluated in the present study.
Data in the present study were collected from 1 referral institution, and subsequent statistical analysis confirmed that the 2 groups were similar in patient and tumor variables. Surgeries were performed over the same time period, with the same suture materials. and by the same surgeons, who were ECVS surgical specialists or ECVS surgical specialists-in-training under the supervision of an ECVS surgical specialist. The relative uniformity of surgeon experience would be expected to mitigate the documented effect of learning curve on complications.24 Despite the retrospective nature of the present study, using data from a single surgical center allowed increased uniformity of surgical procedures, when compared to the only available study assessing incomplete mast cell tumor excision wound healing.21 In addition, aftercare information was available for every patient in this study, eliminating the potential bias created when patients are lost to follow-up.25 Patients with known chronic concurrent conditions (endocrinopathies or neutropenia) or receiving medical therapies (exogenous glucocorticoids or chemotherapy), which have been implicated in delayed wound healing, were excluded from the study population to mitigate the potential effects on patient wound healing.26 As such, patients that had neoadjuvant chemotherapy or prednisolone were not included in the present study to eliminate the potential variable effects of these treatments on wound healing. It is possible that the use of neoadjuvant treatment could have permitted marginal resection without the use of flap reconstruction techniques,27 which had a higher wound healing complication rate than direct apposition in the present study.
Following standard oncological principles, flap wound reconstruction is avoided where possible at the time of initial tumor resection to avoid tumor seeding and to minimize the size of any future radiotherapy field. However, the successful use of skin flaps prior to radiation therapy, albeit with high associated morbidity, has been previously documented.28 As in the present study, there are situations when single-stage resection and reconstruction are performed due to patient anesthesia, patient or owner bandage compliance, or owner financial considerations. Where tumor resection and flap reconstructive techniques are employed in a single surgery, it is imperative that surgical kit and surgeon gloves be changed between steps to minimize the chance of tumor seeding. The flap reconstruction used within this study were all single-stage local subdermal plexus. The total complication rates for the subdermal plexus flaps used in our study (29%) was similar to what is previously reported for skin-fold advancement flaps (25%).29 Cases with axial pattern flap reconstruction were omitted from our study due to their low numbers and the higher reported complication rates of axial pattern flaps and the specific complication of distal flap tip necrosis they are associated with.30 The delay phenomenon suggests that flaps raised and transferred in 2 or more steps may be more likely to survive without such necrosis but the time lag between surgeries would naturally be expected to delay the time to complete healing from initial excision and therefore, the time to the delivery of adjuvant therapy.31 Although reconstructive techniques may allow an increased lateral margin to be obtained, they do not commonly influence the possible deep margin acquired during tumor resection, so their value in light of their increased morbidity in areas where there is a lack of distinct deep fascia (eg, tarsometatarsal region) is questionable.32
The study population did not include patients undergoing other distant direct or free skin grafts, so no recommendations can be made regarding their specific use. An alternative to flap reconstruction or partial reconstruction following intentional marginal excision is complete second intention healing, but potential disadvantages of this technique could include wound contracture and joint dysfunction (if wounds are located over a joint) and particularly relevant for where adjuvant therapies are planned: delayed healing, and incomplete epithelialization.33 In the present study, the use of a subdermal plexus flap for closure was significantly associated with increased complications and healing time. This finding may be unexpected as the flap is used to allow closure of the excision site without tension and it was considered that the flaps may not have permitted enough tension relief. However, only 2 cases suffered partial dehiscence without either a self-trauma, initial seroma, or purulent discharge so it was considered that increased patient discomfort, increased dead space, excess motion at the surgical site, or a longer surgery time to allow flap creation could have been contributing factors.
Delayed healing in these patients would be expected to delay planned adjuvant therapy. The exact effect of delay in initiation of radiotherapy on local recurrence rate, rate of metastasis, and overall survival in dogs remains unclear. The published prognosis for dogs with MCT and STS treated with surgery and radiation is generally good but is difficult to interpret given that incompletely resected tumors do not always result in local recurrence.3,34 Scarpa et al35 supported the use of adjuvant treatment following incomplete resection of MCT and STS, as they found a significantly higher local recurrence rate when incomplete margins were compared with complete margins. The histological tumor free margin required to decrease or eliminate the odds of local recurrence35,36 of MCTs and STSs remains to be determined. As such, it could be argued that for some dogs in the present study, adjuvant therapy may not have carried a benefit and therefore a treatment delay was unlikely to be of prognostic clinical significance.
The authors acknowledge some important study limitations. Due to the retrospective nature of the study, the accuracy and completeness of the medical records was uncertain. There was a variable time to the first postoperative presentation (between 10 and 14 days post-operatively) for dogs with uncomplicated wound healing, and this may have influenced the recorded healing times. The first post-operative healing check following discharge was usually associated with planned suture removal unless there were previous concerns. Physical examination and wound inspection of course cannot truly assess wound healing. To do so, the scars would require excision for histopathology and biomechanical testing but, as ours was a clinical retrospective study, this was not possible.
Another limitation was that the number of dogs that developed complications was low. The possibility of underreporting of complications was considered, and it was thought that major wound healing complications such as dehiscence would be more likely to be reported than minor complications such as mild swelling, which could have resulted in underestimation of the true prevalence of minor complications in the 2 dog groups. An accepted categorization of complications was used to recognize that complications varied in both patient morbidity and owner emotional and financial impact.37,38 However, the division of complications into major and minor complications is generally somewhat influenced by the surgeon’s subjective clinical decision-making and is therefore to some extent biased.
In conclusion, marginal excision of cutaneous MCTs was not associated with a higher rate of complication or prolonged wound healing than marginal excision of STSs. The use of flap reconstruction in skin closure may delay healing and planned adjuvant therapy. Owners should be counseled regarding these risks and, where appropriate and feasible, surgery without reconstruction could be considered.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org
Acknowledgments
The authors received no funding or support and declare no conflicts of interest. Preliminary findings were presented as an abstract at the 26th ECVS Annual Scientific Meeting in Edinburgh.
The authors thank Dr. Sarah Gibson for statistical support.
References
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