Does the extent of the surgical margin affect the likelihood of local recurrence in Patnaik grade I or II cutaneous mast cell tumours?

s 31 9 5 10 1 6 PubMed 99 58 14 19 0 8 Total relevant papers when duplicates removed 8


Strength of evidence
(2019) study, only 1/30 low-grade cutaneous mast cell tumors developed local recurrence. Therefore, there is some evidence that conservative surgical excision is sufficient to achieve local control with low recurrence rates

Conclusion
There is increasing evidence in the literature for conservative surgical excision of grade I and II MCTs, but because the quality of evidence is low, no clear recommendations can be made. Further studies are needed to determine recommendations for surgical excision of cutaneous MCTs based on the biological characteristics of the tumour and the completeness of histologic margins How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient's circumstances and owners' values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

The evidence
The overall quality of evidence is low, consisting predominantly of retrospective observational studies (Sequin et al., 2001;Simpson et al., 2004;Pratschke et al., 2013;Chu et al., 2020;Saunders et al., 2020;and Itoh et al., 2021) and no randomised prospective clinical trials. Two prospective observational clinical studies (Fulcher et al., 2006;and Milovancev et al., 2019) showed a low recurrence rate, but both consisted of a very small sample size (23 and 30 cutaneous MCTs, respectively). • Histological margins: were categorised as complete, complete but close (tumour cells within 1 mm of surgical margin), or incomplete (tumour cells at the surgical margin). • Follow-up method: Follow-up information was obtained via reassessment at the clinic or telephone calls to referring veterinarians or owners. • Median follow-up time 540 days (range, 77-1,804 days). 46/55 (84%) dogs were free of MCT during the study period.

Limitations:
• Small sample size -risk of type II error.
• Two dogs had amputation for definite treatment and local recurrence was impossible to assess in these two cases. • No clear definition of exact margins as a range was given (2-3 cm) and lacked assigned groups. • Non-objective follow-up in some cases (client follow-up)potential risk of local recurrence underestimated. • Definition of local recurrence in relation to the original scar was not specified -the risk of some local recurrences being classified as de novo. • Retrospective nature -some medical records are incomplete (e.g., tumour size) and therefore cannot provide information for tumours larger than 4 cm. • No definite diagnosis of local recurrence with cytology or biopsy. • Prognostic relationship between histopathological status of surgical margins and recurrence could not be determined because the number of local recurrences was small (5%), and the classification system of histological margins differed from other studies and was therefore difficult to compare. • Participants' characteristics not homogeneous -surgery was performed as revision in some cases (21 dogs).

Simpson et al. (2004)
Population: Client-owned dogs diagnosed with cutaneous mast cell tumours (MCTs) based on cytological examination of fine needle aspirates, at Animal Medical Center, New York, USA -time interval not reported. • Histological margins: were categorised as complete, complete but close (tumour cells within 1 mm of surgical margin), or incomplete (tumour cells at the surgical margin). • Follow-up methods: Follow-up information was obtained via reassessment at the clinic or telephone calls to referring veterinarians. • Local recurrence: Disease-free interval was defined as the interval from the date of tumour excision to the date of local recurrence. • Survival time was defined as the interval from the date of tumour excision to the date of death.
Study design: Prospective case series.

Limitations:
• This study has a small sample size and is prone to type II error. • This study does not include MCTs on the face or inguinal and perineal regions, and no recommendation can be made for these locations. • One dog in which MCTs were detected within 1 mm of the deep margin received full-course radiation therapy; therefore direct comparison cannot be made for this patient. • Although there is no statistical correlation between tumour diameter and completeness of excision, most tumours in this study were small. • The period during which participants were enrolled in the study was not mentioned. • Inconsistent method of follow-up.

Intervention details:
• Surgical margins: MCT removed with 3 cm margins and one fascial plane deep margin. o Prior to removal, the skin was marked at 1, 2, and 3 cm from the tumour margin at 0°, 90°, 180°, and 270°. o Tumours were affixed to cardboard to recreate their original shape. o Tissues were fixed in formalin and eight 1 cm long fullthickness tissue samples were taken at 3 cm margins. o Four 1cm long full-thickness tissue sections were obtained at the 1cm and 2cm margins. o All tissue margins were examined by one boardcertified pathologist. • Tumour grading: All tumours were graded by two pathologists using the Patnaik system. • Adjuvant treatment: Some dogs had corticosteroids, but no more information was given. • Histological margins were categorised as complete, complete but close (tumour cells within 1 mm of surgical margin), or incomplete (tumour cells at the surgical margin). • Follow-up method: Follow-up information was obtained via reassessment at the clinic or telephone calls to referring veterinarians. • Local recurrence was defined as the development of an MCT at or within 2 cm of the original surgical site. • Disease-free interval: time of surgery to local recurrence.

Study design: Prospective clinical trial.
Outcome studied: • Local recurrence.

Main findings: (relevant to PICO question):
• o There was no recurrence in two of the grade II tumours with incomplete margins, although one had revision surgery 2 weeks after the first excision. o All had complete deep margins. • Local recurrence: None of the dogs had local recurrence.
• Follow-up time: The median follow-up interval for all dogs was 379 days (range, 51-538 days).

Limitations:
• This study has small sample size and is prone to type II error.
• This study does not include MCTs on the face or inguinal and perineal regions, and no recommendation can be made for these locations. • One dog with incompletely excised MCT received additional surgery in 2 weeks therefore direct comparison cannot be made. • Inconsistent method of follow-up (either clinical examination or telephone update). • The period when participants were enrolled in the study was not mentioned.

Pratschke et al. (2013)
Population: Dogs with cutaneous and subcutaneous mast cell tumours (MCTs) were diagnosed either with cytological or histopathological examination at the University of Glasgow between 2008 and 2012.

Sample size: 40 dogs (47 MCT [41 cutaneous and six subcutaneous]).
Intervention details: • Surgical margins: Lateral margins equivalent to the widest measured diameter of the tumour and a minimum depth of one well-defined fascial plane. If tumour size exceeded 4 cm then a fixed 4 cm lateral margin was taken. • Tumour grading: Grading based on Patnaik and Kiupel system. • Histological margins: Margins were considered clear when the distance between neoplastic cells and non-neoplastic tissue was > 1 mm; otherwise, they were considered incomplete. • Follow-up methods: retrieved from clinical records and through contact with the referring veterinarians and dog owners.
Study design: Retrospective case series.
Outcome studied: The margin of excision (complete vs incomplete excision as histologically determined) was compared between conservative-and wide-margin groups.  (11), head (five), and neck region (three). The study did not specify the location of the remaining 10 tumours. • Tumour grading: o All tumours were histologically classified as grade I or II by the Patnaik system. o Tumours in the wide-margin group were more likely to be classified as grade II (vs grade I) than were tumours in the conservative-margin group. • Adjuvant treatments: One dog in the wide margin group and two in the conservative margin group had preoperative prednisone administration. • Histological tumour-free margins: o Conservative group: 43/46 (93%). o Wide margin group: 34/37 (92%). • The risk ratio met the criterion for noninferiority.

Limitations:
• Lack of randomisation: More tumours grade II in the wide margins group which could induce bias to the study.

Intervention details:
• Surgical margins: The width of proportional margin excision was based on the largest lateral diameter of the mass up to a level of 2 cm. If the tumour diameter was greater than 2 cm, the lateral margins that were used to excise the mass were limited to 2 cm. The tumours were excised in an en bloc manner with the proposed lateral surgical margins and a minimum of at least one fascial plane as deep margin. Study design: Retrospective cohort study.

Main findings: (relevant to PICO question):
• Tumour diameter: o Low-grade MCTs: 42 were < 10 mm in diameter, and 46 being = 10 mm in diameter. tumour grade and HTFM size. o No significant association was evident between the tumour size groups and the HTFM size groups. • Recurrence rate: 3/100 tumours (3%) with a median followup period of 593 days (range 180-1460 days) with none on the low-grade group and three on the high-grade group 3/12(25%). • Of the incompletely excised masses, four were low-grade, and one was high-grade and only the high grade recurred. • 45 tumours had neoadjuvant prednisolone and chlorpheniramine administered but there was no significant association between the rates of complete excision between tumours that had neoadjuvant therapy compared to those that did not.

Limitations:
• Retrospective nature and as such inability to standardise follow-up assessment for recurrence. • Some dogs had neoadjuvant prednisolone which could affect tumour size, completeness of excision, and margin assessment. • 18 dogs were excluded from the margin assessment as no report on histological margins in the clinical records. • Tumour size may affect the completeness of excision as this relationship was close to statistical significance -potentially with increased sample size groups, the relationship would be more obvious. • Eight dogs lost to follow-up before the 365 days but all of them were grade I. • Limitation is also the radial trimming of margins as less sensitive than the tangential method to detect residual tumours at the margins. Study design: Retrospective case series.

Limitations:
• Local recurrence distance in relation to surgical scar was not specified. • Small sample size -prone to type II error. • Only tumours with small size were included.

Appraisal, application and reflection
Historically, it has been recommended that mast cell tumours (MCTs) independently of grade, must be excised with 3 cm lateral margins and one fascial plane as deep margin. However, evidence to support this recommendation is lacking, especially for grade I and II MCTs. Recent literature suggests that the removal of these low-grade tumours with 2 cm lateral margins and one deep fascial plane, is sufficient to achieve local control and does not increase the incidence of local recurrence (Simpson et  In the study by Seguin et al. (2001), 2-3 cm margins were used to remove MCTs, however, the authors did not divide the dogs into groups in terms of margins, so no direct comparison between conservative and wide excision is possible. In this study, only 5% (three tumours) recurred locally; however, the authors based their follow-up not only on clinical examinations but also on referring veterinarians or telephone updates from clients. There is a possibility that this local recurrence rate is underestimated, as some recurrences may be missed by clients. The authors also included dogs with scar tissue of previously incompletely excised MCTs, which makes the study population not homogeneous. In addition, two dogs had an amputation as definite treatment, and as such local recurrence could not be evaluated in these dogs. Other limitations of this study include its retrospective nature, which may mean that some information was not recorded in the medical records.
Two later studies, one by Simpson et al. (2004) and Fulcher et al. (2006), investigated the removal of grade I and II MCTs with 2 cm lateral margins. Both studies suffer from small sample sizes, which predispose them to type II statistical error. When we combine both studies for a total number of 46 MCTs (seven grades I and 39 grade II), 44/46 MCTs (95%) were completely excised at 2 cm lateral surgical margin. Only two dogs, in the Fulcher et al. (2006) study, had incomplete histological margins and none of them suffered local recurrence; however, one dog received revision surgery 2 weeks later. In both studies, no local recurrence was noted at a median follow-up of 351 days and 379 days, respectively. Based on these studies, it was suggested that a surgical dose of 2 cm lateral margins and one fascial plane deep should be sufficient to achieve local control without increased rates of local recurrence for grade I and II MCTs. Pratschke et al. (2013) first described the approach of surgical excision based on the proportional margin of the tumour. In this study, masses were resected with a lateral margin equal to their widest diameter, with a maximum lateral margin of 4 cm and a well-defined deep fascial plane. Complete excision was achieved in 40/47 (85%) of cases, and although 7/47 (15%) of excised tumours had dirty margins, only one recurred locally during a median follow-up of 420 days. This was a completely excised, grade III MCT, highlighting the fact that achieving local control is not only influenced by the completeness of histological margins but also depends on the biological behaviour of the tumour. This study had a small sample size and a relatively short median follow-up time, which may have influenced the local recurrence rate. Furthermore, two of the dogs with incomplete margins had adjuvant treatments and another dog with incomplete margins died from gastric dilatation-volvulus 1 day post-surgery. One advantage of this study is that it included tumours in difficult locations such as the face, distal extremities, inguinal and preputial regions.  margins in both groups (93% and 92%, respectively). The authors concluded that this conservative approach was not inferior to the wide approach in achieving histologically free margins. The main limitation of this study was that the outcome measured was histologically free margins and not local recurrence. Milovancev et al. (2019) showed in a prospective clinical study with a follow-up of 2 years that narrow histological margins (1 mm) do not always correlate with local recurrence. In this study, 30 low-grade MCTs with a mean intraoperative margin of 20 mm were removed and only one recurred. This review suggests that most grade I and II cutaneous MCTs can be safely excised without an increase in the recurrence rate using either 2 cm lateral margins (Simpson et al., 2004;and Fulcher et al., 2006) or the proportional margin approach (Pratschke et al., 2013; Chu et al., 2020; and Saunders et al., 2020) instead of the classic recommendation of wide surgical excision (3 cm lateral margins). Nevertheless, the overall evidence is low and further studies, preferably multi-institutional studies with larger study populations, are needed to provide higher quality of evidence. These recommendations do not apply to high-grade MCTs, which are biologically more aggressive, locally invasive, and more likely to metastasize. Similarly, these recommendations must be used with caution for subcutaneous MCTs. There is no grading system for subcutaneous MCTs and many times their actual margins are not easily distinguished due to their subcutaneous origin and surrounding oedema. Studies by Pratchke et al. (2013) and Itoh et al. (2021) contained subcutaneous MCTs, but due to their low numbers, no correlation between surgical margins and local recurrence could be made.