Cutaneous MCTs are one of the most common neoplasms in dogs, with an estimated prevalence of 0.27% among dogs evaluated at primary care veterinary practices in England.1 Among dogs identified with cutaneous neoplasms at veterinary medical teaching hospitals in the United States, the estimated prevalence of MCTs is 11%.2
Excision is the treatment of choice for dogs with localized, nonmetastatic MCTs.3 Following tumor excision, gross surgical margins are marked and a histologic assessment of the excised tumor is performed to assess the completeness of the excision. Further treatment recommendations, including the need for revision surgery, are determined by the outcome of this assessment.3 Incomplete tumor excision (ie, mast cells identified at the surgical margin on histologic assessment) is associated with an increased risk of local recurrence,4 shorter disease-free interval,5 and shorter median survival time, compared with complete excision.6 Large MCTs and less experienced surgeons have been identified as risk factors for incomplete excision.7
The size of lateral surgical margins necessary to achieve tumor-free histologic margins for cutaneous MCTs in dogs has not been definitively established. Traditionally, 3-cm lateral surgical margins have been recommended.8 However, more conservative surgical margins have been evaluated. In a prospective study,9 5 of 20 (25%) grade II (Patnaik system) cutaneous MCTs were incompletely excised from dogs when 1-cm lateral surgical margins were used, but all were completely excised when 2-cm lateral surgical margins were used. Another study10 of grade I and II MCTs in dogs showed that 2 of 23 (9%) tumors were incompletely excised when 2-cm lateral surgical margins were used, but no 3-cm-margin comparison group was included. In a study11 in which the proportional surgical margins approach (lateral surgical margin equal to tumor diameter) was evaluated in dogs, excision of 47 cutaneous and subcutaneous MCTs resulted in incomplete excision for 7 (15%) tumors, but this study also lacked a comparison group. Finally, a study12 of dogs that underwent excision of cutaneous MCTs showed that 4 of 69 (6%) dogs in which histologic lateral margins of < 1 cm were achieved later developed metastatic disease, compared with 0 of 43 (0%) dogs in which histologic lateral margins of ≥ 10 mm were achieved; however, this difference was not significant. Given the aforementioned negative association between incomplete tumor excision and patient outcome, additional evidence is needed to assist veterinary surgeons in deciding between whether to use 3-cm lateral surgical margins or a more conservative approach.
The objective of the study reported here was to determine whether a conservative approach to lateral surgical margins was noninferior to a 3-cm (wide-margin) approach for excision of cutaneous MCTs in dogs. For the conservative-margin group, we elected to include tumors excised with lateral surgical margins equal to the tumor diameter for tumors < 2 cm in diameter and lateral surgical margins of 2 cm for tumors ≥ 2 cm in diameter. We hypothesized that the conservative-margin approach would not yield a significantly lower proportion of excised tumors with tumor-free histologic margins than achieved with the wide-margin approach or, more specifically, that the RR for complete excision of the tumor with the conservative- versus wide-margin approach would be no lower than 0.9.
Materials and Methods
Cutaneous MCTs that had been excised from dogs between January 1, 2007, and December 31, 2017, at the Cornell University Hospital for Animals were identified by a search of the pathology department's database; the results of this search were then cross-referenced with hospital medical records to obtain clinical data for identified dogs. Tumors identified in this manner were excluded from the study if the medical record did not contain tumor diameter information, a sufficiently detailed surgery report, or the required information from the histologic report (ie, histologic tumor grade and assessment of histologic tumor margins). Tumors were also excluded if the approach to lateral surgical margins did not conform with the study hypothesis, a deep fascial plane was not obtained en bloc with tumor excision, the excised mass represented local recurrence or scar revision of a previously excised MCT, or tumors were classified as histologic grade III (Patnaik system13) or high grade (Kiupel system14).
Data were obtained on patient signalment, tumor size and location on the body, tumor quantity (single vs multiple simultaneous MCTs), patient comorbidities, prednisone administration in the 7 days prior to and at the time of tumor excision, staging test results, surgical report details, histologic tumor margin status (complete vs incomplete), and histologic tumor grade. A single investigator (MLC) extracted all study data from the medical records, which included interpretation of the histologic report findings for study purposes.
Each tumor included in the study had been excised with a deep surgical fascial margin by a board-certified veterinary surgeon or surgical resident. Lateral surgical margins were defined as the distance from the perceived lateral limit of the tumor to the point where the skin was incised. Tumors were assigned to a conservative-margin group if they had been excised with lateral margins that were 2 cm for tumors ≥ 2 cm in diameter or equal to the tumor diameter (proportional) for tumors < 2 cm in diameter (eg, a tumor 7 mm in diameter was excised with 7-mm lateral margins). Tumors were assigned to a wide-margin group if they had been excised with lateral margins of 3 cm, regardless of tumor diameter.
Histologic assessments had been performed by board-certified veterinary pathologists. Following formalin fixation, each mass had been sectioned such that 4 lateral and associated deep histologic margins could be evaluated on 4 slides, according to the standard operating procedure for the pathology department during the study period. An investigator (MLC) recorded the histologic tumor margin status as complete excision when results of microscopic examination revealed no mast cells with characteristics suggestive of neoplastic behavior at the lateral or deep edge of the section, whether individually scattered or as part of the neoplasm, as defined by Pratschke et al.11 In all other instances, the histologic tumor margin status was recorded as incomplete excision. Tumors identified with a histologic tumor grade of intermediate (Kiupel system) were classified as grade II (Patnaik system) for the purposes of this study. This provided a histologic tumor grade of I or II for each tumor, which was how this variable was coded for all subsequent analyses. Results of cytologic examination of fine-needle aspirate specimens from a regional lymph node (when performed) were classified as positive, negative, or equivocal for evidence of metastasis.
Statistical analysis
We estimated that a sample size of at least 30 tumors in each treatment group (conservative margin and wide margin) would provide the analysis with a power of at least 80% to show the noninferiority of the conservative-margin approach to the wide-margin approach if it truly existed. The assumption was made that histologic tumor margins would indicate complete excision for 92% of the tumors in the widemargin group, and an acceptable maximum risk probability difference of 20% was chosen.
Normality of continuous variables was assessed with the Shapiro-Wilk test. Data were reported as mean (SD) when normally distributed and as median (range) when nonnormally distributed. Comparisons of continuous variables between treatment groups (ie, conservative- and wide-margin groups) were performed by use of the Student t test for normally distributed variables and the Wilcoxon rank sum test for nonnormally distributed variables. Frequency distributions of categorical variables were compared between groups (unit of analysis was tumors or dogs, as applicable) by use of the Fisher exact test. Univariable logistic regression was performed to assess associations between binary outcomes (histologic tumor margin status [ie, complete vs incomplete excision] and histologic tumor grade [grade I vs II]) and categorical variables (treatment group [conservative vs wide margin] and quantity of MCTs [ie, single vs multiple simultaneous]).
Multivariable logistic regression was used to assess the potential association between treatment group status and histologic tumor margin status after adjustment for the potential confounding effect of histologic tumor grade (as identified by univariable analyses). Pearson and deviance residuals were visually examined to check for outliers that may have influenced the model results. The goodness of fit of the model was assessed with the Hosmer-Lemeshow test. A method previously described by Zhang and Yu15 was used to convert ORs to RRs for subsequent noninferiority hypothesis testing. Robust SEs of the model coefficients were used to address the lack of independence in the data (ie, multiple simultaneous MCTs in a dog). Proportions were compared between treatment groups by use of the z test. The RR for the primary outcome measure (histologic tumor margin status) was calculated as the probability of complete excision in the conservative-margin group divided by the probability of complete excision in the wide-margin group. The 95% CI for the RR was calculated by use of a technique described by Gart and Nam.16 The noninferiority margin for the RR was set at > 0.9, implying that noninferiority would be established if the data indicated that the true risk of complete excision with the conservative-margin approach was at worst 90% of that for the wide-margin approach.
Values of P < 0.05 were considered significant for all analyses. Descriptive analysis and intergroup comparisons were performed with statistical software.a Noninferiority testing and sample size calculation were performed with other statistical software.b
Results
A total of 623 cutaneous MCTs were identified in the pathology department's database, of which 83 (from 68 dogs) met the study inclusion criteria (Figure 1). The conservative-margin group consisted of 46 tumors from 38 dogs, and the wide-margin group consisted of 37 tumors from 30 dogs.
Flow diagram depicting the identification, inclusion, and exclusion of grade I or II cutaneous MCTs excised from dogs between January 1, 2007, and December 31, 2017, in a retrospective study to investigate whether a conservative (≤ 2-cm) approach to lateral surgical margins was noninferior to a wide (3-cm) approach for achieving tumor-free histologic margins.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
Flow diagram depicting the identification, inclusion, and exclusion of grade I or II cutaneous MCTs excised from dogs between January 1, 2007, and December 31, 2017, in a retrospective study to investigate whether a conservative (≤ 2-cm) approach to lateral surgical margins was noninferior to a wide (3-cm) approach for achieving tumor-free histologic margins.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
Flow diagram depicting the identification, inclusion, and exclusion of grade I or II cutaneous MCTs excised from dogs between January 1, 2007, and December 31, 2017, in a retrospective study to investigate whether a conservative (≤ 2-cm) approach to lateral surgical margins was noninferior to a wide (3-cm) approach for achieving tumor-free histologic margins.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
Dogs
The 68 included dogs were most frequently identified as Labrador Retriever (n = 14), mixed-breed dog (12), Boxer (9), Pug (6), and Boston Terrier (4); there was no difference (P = 0.16) in breed distribution between the 2 treatment groups. The dogs included 24 males (22 neutered and 2 sexually intact) and 44 females (42 spayed and 2 sexually intact), with no difference (P = 0.95) in sex distribution between the 2 treatment groups. There was no difference between treatment groups in dog age, the likelihood of having multiple simultaneous (vs single) cutaneous MCTs, or the frequency of preoperative prednisone administration (Table 1). No other preoperative chemotherapeutics were administered. Among the 68 dogs, 56 had single MCTs, 9 had 2 MCTs, and 3 had 3 MCTs. Dogs in the conservative-margin group had a lower body weight (P < 0.001) than did dogs in the wide-margin group.
Characteristics of 68 dogs with grade I or II cutaneous MCTs that were excised with lateral surgical margins equal to tumor diameter (proportional) for tumors < 2 cm and lateral surgical margins of 2 cm for tumors ≥ 2 cm in diameter (conservative-margin group) or with lateral surgical margins of 3 cm (wide-margin group).
| Characteristic | Wide-margin group (n = 30) | Conservative-margin group (n = 38) | P value |
|---|---|---|---|
| Age (y) | 7.5 (2.9) | 7.9 (2.8) | 0.53 |
| Body weight (kg) | 35.7 (7.2-54.6) | 20.9 (5.5-57.3) | < 0.001 |
| Preoperative prednisone administration | 1 (3) | 2 (5) | 0.72 |
| Multiple simultaneous MCTs | 5 (17) | 7 (18) | 0.85 |
Age is reported as mean (SD) and body weight as median (range). Other variables are reported as number (%) with the indicated characteristic.
Thoracic radiography was performed for all 68 dogs, and results were negative (n = 67) or equivocal (1) for evidence of metastatic disease. Cytologic examination of fine-needle aspirate specimens from the liver, spleen, or both was performed for 5 dogs, and results were negative (n = 4) or equivocal (1) for similar evidence.
MCTs
The 5 most common tumor locations were the proximal aspect of the thoracic or pelvic limb (n = 29) or the thoracic (25), abdominal (11), head (5), or neck (3) region. There was no difference (P = 0.95) in the frequency distribution of tumor location between the 2 treatment groups.
Median (range) tumor diameter for the wide-margin and conservative-margin groups was 1 cm (0.2 to 7.0 cm) and 1.0 cm (0.1 to 4.0 cm), respectively (P = 0.10). The frequency distributions of tumor diameter for the 2 treatment groups were summarized (Figure 2).
Frequency distribution of diameter measurements for MCTs in the conservative-margin group (A; n = 46) and wide-margin group (B; 37) of Figure 1.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
Frequency distribution of diameter measurements for MCTs in the conservative-margin group (A; n = 46) and wide-margin group (B; 37) of Figure 1.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
Frequency distribution of diameter measurements for MCTs in the conservative-margin group (A; n = 46) and wide-margin group (B; 37) of Figure 1.
Citation: Journal of the American Veterinary Medical Association 256, 5; 10.2460/javma.256.5.567
All tumors were histologically classified as grade I or II by the Patnaik system; 3 of the 13 grade I tumors were also assigned a low grade by the Kiupel system, and 13 of the 70 grade II tumors were also assigned a low grade by that system. Tumors in the wide-margin group were more likely to be classified as grade II (vs grade I) than were tumors in the conservative-margin group (36/37 [97%] and 34/46 [74%], respectively; P = 0.01).
Cytologic examination of fine-needle aspirate specimens from regional lymph nodes was performed for 9 tumors in the conservative-margin group and 11 tumors in the wide-margin group; there was no difference (P = 0.40) in the frequency distribution of the results between the conservative-margin group (5 negative or nondiagnostic, 2 equivocal, and 2 positive) and the wide-margin group (3 negative or nondiagnostic, 4 equivocal, and 4 positive).
Tumor-free histologic margins (indicating complete excision) were recorded for 34 of 37 (92%) tumors in the wide-margin group and 43 of 46 (93%) tumors in the conservative-margin group. Histologic tumor margin status was not associated with treatment group status (RR, 1.02; 95% CI, 0.89 to 1.19). For tumors with a histologic margin status recorded as incomplete excision, there was no difference (P = 0.40) in the proportion with incomplete excision identified at lateral (vs deep) surgical margins between the 2 treatment groups (2/3 in both groups). Among the 83 tumors, histologic tumor margin status (complete vs incomplete) was not associated with tumor quantity (single vs multiple simultaneous MCTs; P = 0.68) or histologic tumor grade (grade I vs grade II; P = 0.65). Tumors that were 1 of multiple simultaneous MCTs were more likely to be histologically classified as grade I than were single MCTs (OR, 4.3; 95% CI, 1.2 to 14.8; P = 0.02).
Noninferiority assessment
The RR (1.02; 95% CI, 0.89 to 1.19; P = 0.03) met the criterion for noninferiority. Given that the noninferiority margin for the RR was set at > 0.9, this was interpreted as indicating with 95% confidence that the true RR for complete excision with the conservative- versus wide-margin approach would be 0.9 at the lowest, corresponding to a maximum tolerated decrease in the probability of complete excision of 9.2% from 92% (percentage of tumors with complete excision in the wide-margin group), which would be equivalent to a minimum probability of complete excision of 82.8% (ie, 92% – 9.2%) with conservative lateral margins. The RR did not change after adjustment for the potential confounding effect (ie, difference between treatment groups) of histologic tumor grade (RR, 1.02; 95% CI, 0.78 to 1.08).
Discussion
In the observational study reported here, evidence of noninferiority was found for a conservative approach to lateral surgical margins (2-cm margins for tumors ≥ 2 cm in diameter or margins equal to tumor diameter margin for tumors < 2 cm in diameter), compared with a wide approach (3-cm margins, regardless of tumor diameter), for complete excision of grade I or II (Patnaik system) cutaneous MCTs in dogs. The proportion of grade II (vs grade I) tumors differed between the 2 treatment groups. Tumors that were 1 of multiple simultaneous MCTs were more likely to be classified as grade I than were single MCTs, suggesting that quantity of MCTs may have been a proxy variable for histologic tumor grade.
We were concerned that the lower proportion of grade II tumors in the conservative-margin group might have biased the results toward a finding of noninferiority, given that grade I tumors are less infiltrative. This prompted us to estimate the RR after adjustment for histologic tumor grade. However, the adjusted and unadjusted RRs were similar, which helped to mitigate this concern. The finding of noninferiority for the use of conservative (vs wide) lateral surgical margins in the present study was consistent with findings of previous studies,9,10 which showed high rates of complete excision when lateral surgical margins of ≤ 2 cm were used. When conservative lateral surgical margins were used, the point estimate for risk of incomplete excision in a previous study10 (2/23 [9%]) was similar to that in the present study (3/46 [7%]).
Although noninferiority studies have not been commonly reported in veterinary medicine, their use offers several advantages. A lack of a significant difference in frequency of an outcome between 2 treatment groups is not evidence of equivalence of group treatment, given that a nonsignificant finding can be influenced heavily by group sample size. Although it is not statistically possible to prove that 2 treatments are identical in effect, it is possible to establish that a new treatment is not worse than a control treatment by a predefined acceptably small amount with a given degree of confidence. The null hypothesis in a noninferiority study states that the primary end point for the new treatment is worse than that for the control treatment by the prespecified amount; rejection of the null hypothesis at a prespecified level of significance is used to support the conclusion of noninferiority for the new treatment.17
Our justification for performing a noninferiority study rather than a more traditional superiority study was that we believed that use of lateral surgical margins of ≤ 2 cm would be noninferior to use of 3-cm margins for complete excision of grade I and grade II cutaneous MCTs but would offer the advantage of a lower risk of postoperative pain or complications. For the present study, we selected a low noninferiority margin (> 0.9) for the RR. It has been suggested that the choice of a noninferiority margin in this type of study is a matter of clinical judgment governed by the maximum loss of efficacy one is willing to accept in return for the advantages of the new treatment.18
Clinicians considering use of the results reported here as additional evidence to justify switching from lateral surgical margins of 3 cm to those of ≤ 2 cm must be willing to accept a tradeoff between the worst-case possibility of a 10% increase in the risk of incomplete MCT excision and the potentially lower risk of postoperative pain or complications. Given that 8% of tumors included in the present study were incompletely excised when 3-cm lateral surgical margins were used, this increase in risk could translate to an additional 9 dogs/100 with incompletely excised tumors when lateral surgical margins of ≤ 2 cm are used. It should also be noted that the available evidence for justifying the use of conservative lateral margins, including results of the present study, is observational in nature. Randomized controlled trials are needed before practice-changing recommendations can be made. Until the results of such trials are available, it may be prudent for clinicians contemplating a conservative-margin approach for 1-stage excision and reconstruction of large MCTs for which a recut would not be feasible to ensure, at a minimum, that the tumor is grade I or II (Patnaik system) or low grade (Kiupel system). The present study, together with previous observational studies,9–12 provides evidence for the use of a conservative-margin approach, but only for grade I or II or low grade MCTs.
The appropriate method for defining tumor-free histologic margins (indicating complete excision) remains controversial. For MCTs in dogs, evidence of complete excision has been variously defined as identification of tumor cells > 5 mm,19 > 3 mm,4 > 2 mm,20 or ≥ 1 mm3,10,21 from the edge of the fixed section and no tumor cells at the edge of the fixed section.5,6,9,11,12,22 The number of sections that should be examined for each tumor and whether this should vary with tumor size have also not been determined. By cumulative probability, the more sections that are examined, the greater the chance of identifying histologically incomplete margins. Histologic margin width has also been shown to be poorly correlated with surgical margin width and is affected by specimen preparation methods,23,24 calling into question the validity of basing treatment decisions on histologic measurements made in the absence of standardized techniques.
This present study had several limitations. Perhaps the greatest of these was that dogs with high-grade or grade III tumors were excluded, yet in clinical settings, frequently the histologic tumor grade is not known prior to excision. Two cytologic grading schemes20,25 have been published, and hopefully, preoperative prediction of tumor grade will become possible as these schemes undergo validation and become more widely used. In the interim, caution should be exercised when extrapolating our findings to dogs with an unknown histologic tumor grade. An additional limitation was that the study treatment was not randomly assigned, resulting in differences in certain characteristics between the conservative- and wide-margin groups (eg, differences in body weights and proportions of grade II [vs grade I] tumors). Surgeons may have selected a more conservative approach for tumors that appeared less aggressive on the basis of factors such as medical history or gross appearance of tumor, and some of these factors may be unmeasurable. Despite adjustment for treatment group differences in histologic tumor grade in our analysis, the potential for a biased result remained. The dogs of the present study represented a subset of dogs with MCTs for which complete data were available, which may have also resulted in selection bias. Furthermore, the outcome of interest (ie, tumor-free histologic margins), although meaningful to surgeons and dog owners, essentially acts as a surrogate for tumor recurrence, which we did not assess. We also were unable to assess potential effects of any lack of consistency among the multiple pathologists who processed tissue specimens and assessed histologic tumor margins and grades over the study period. Finally, given the retrospective nature of the study, we were unable to accurately assess other outcomes, such as postoperative pain and incisional complications.
The tumors included in the present observational study provided adequate power to assess the noninferiority of a conservative (≤ 2-cm) approach to lateral surgical margins, compared with a wide (3-cm) approach, for excision of grade I or II cutaneous MCTs. Results suggested that the conservative-margin approach was not significantly worse than the wide-margin approach in these dogs and provided more evidence to support the idea that low rates of incomplete tumor excision can be achieved with conservative surgical margins. However, clinical trials that include information on tumor recurrence and patient survival rates for these 2 approaches are needed.
Acknowledgments
No external funding was used for this study. The authors report that there were no conflicts of interest.
ABBREVIATIONS
| CI | Confidence interval |
| MCT | Mast cell tumor |
| RR | Risk ratio |
Footnotes
Stata, version 13.0, StataCorp, College Station, Tex.
NCSS12, NCSS LLC, Kaysville, Utah.
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