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

a Knowledge Summary by

Christos Dorlis DVM AFHEA MRCVS ^1*

¹Medivet 24 Hour Enfield, 673 Hertford Road, Enfield, EN3 6NH
^*Corresponding Author (chrisdorlis@gmail.com)

Clinical scenario

A 4 year old neutered male Pug presents with a 1 cm cutaneous mass in the left flank region. The owner reports that the mass has been there for 3 months and does not change in size. Cytologic examination suggests a mast cell tumour (MCT). Blood work and abdominal ultrasound were unremarkable. What margin would you ideally excise this mass?

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).

Summary of the evidence

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 al., 2004; Fulcher et al., 2006; Chu et al., 2020; Milovancev et al., 2019; and Saunders et al., 2020).

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.

Based on the original work by Pratchke et al. (2013), two recent studies used a modified proportional margins approach for MCT excision. Chu et al. (2020) compared the completeness of excision (histologically free of tumour margins) after conservative surgical excision (excision with lateral margins equal to or smaller than 2 cm) and wide surgical excision (3 cm lateral margins) and showed a similar percentage of histologically free 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.

Saunders et al. (2020) used a similar approach to Pratchke et al. (2013) and Chu et al. (2020), where they excised MCTs based on the largest lateral diameter of the mass up to 2 cm and with 2 cm margins for masses greater than 2 cm. This study contains the largest sample size with 100 MCTs but both low-grade (88) and high-grade (12) tumours were included. The local recurrence rate was 3% (3/100), similar to Pratchke et al’s. (2013) study 1/45 (2%) but occurred only in high-grade tumours. None of the low-grade mast cell tumours included in the study recurred locally.

A correlation between conservative versus wide surgical excision and completeness of histological margins could not be established in this review because the classification methods of histologic margins were inconsistent between studies and the sampling methods used by histopathologists were different. In addition, the clinical significance of surgical margins and completeness of excision with the likelihood of metastatic spread could not be evaluated in this review.

Increased tumour size is a significant risk factor for incomplete excision with a 1.4% increase in the risk of incomplete excision per cm² (Monteiro et al., 2011). The studies in this review failed to show a significant association between tumour diameter and completeness of excision and clear recommendations regarding surgical margins and large diameter tumours (>4 cm) cannot be made because most of the tumours in the included studies were small in diameter.

MCTs in muzzle, prepuce, inguinal and perineal areas have been associated with aggressive behaviour (Hillman et al., 2010; and Sfiligoi et al., 2005). In Simpson et al. (2004), the location of the MCT on the hind limb was significantly associated with incomplete excision and in Pratchke et al’s. (2013) study, 5/7 tumours with incomplete margins were located on the limbs. This review cannot evaluate surgical margins and recurrence rates in MCTs in difficult locations such as the muzzle, distal extremities, inguinal and perineal areas due to the small number of these tumours in the study populations.

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.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts accessed via OVID platform (1980–2021) PubMed database accessed via NCBI (1986–November 2021)
Search strategy:	CAB Abstracts: (Dog OR canine OR canines OR bitch OR canid) AND (mast cell tumour OR mast cell tumor) AND (surgical margin OR incomplete margin OR dirty margin OR surgical resection OR surgical excision OR surgery OR margin OR resection) AND (recurrence OR local control OR neoplasm recurrence)   PubMed: (Dog OR canine OR canines) AND (mast cell tumour OR mast cell tumor) AND (surgical margin OR incomplete margin OR dirty margin OR surgical resection OR surgical excision OR surgery) AND (recurrence OR local control OR neoplasm recurrence)
Dates searches performed:	09 Nov 2021

Exclusion / Inclusion Criteria
Exclusion:	Single case reports, duplicate articles, review articles, book chapters, or sections. Articles which did not directly evaluate the relationship between lateral surgical margins and local recurrence. Articles that did not specify the surgical margins at the time of the surgery. Articles not available in the English language.
Inclusion:	Original peer-reviewed articles including case series, observational, or interventional studies which evaluate the relationship of lateral surgical margins in MCT excision and local recurrence.

Search Outcome
Database	Number of results	Excluded – Not relevant to PICO question	Excluded – Surgical margins at the time of the surgery not reported and studies with only subcutaneous MCTs	Excluded – Reviews, case reports and letters	Excluded – Not in English or not available	Total relevant papers
CAB Abstracts	31	9	5	10	1	6
PubMed	99	58	14	19	0	8
Total relevant papers when duplicates removed						8

The author declares no conflicts of interest.

1. Chu, M., Hayes, G., Henry, J. & Oblak, M. (2020). Comparison of lateral surgical margins of up to two centimeters with margins of three centimeters for achieving tumor-free histologic margins following excision of grade I or II cutaneous mast cell tumors in dogs. Journal of the American Veterinary Medical Association. 256(5), 567–572. DOI: https://doi.org/10.2460/javma.256.5.567
2. Fulcher, R., Ludwig, L., Bergman, P., Newman, S., Simpson, A. & Patnaik, A. (2006). Evaluation of a two-centimeter lateral surgical margin for excision of grade I and grade II cutaneous mast cell tumors in dogs. Journal of the American Veterinary Medical Association. 228(2), 210–215. DOI: https://doi.org/10.2460/javma.228.2.210
3. Hillman, L., Garrett, L., de Lorimier, L., Charney, S., Borst, L. & Fan, T. (2010). Biological behavior of oral and perioral mast cell tumors in dogs: 44 cases (1996–2006). Journal of the American Veterinary Medical Association. 237(8), 936–942. DOI: https://doi.org/10.2460/javma.237.8.936
4. Itoh, T., Kojimoto, A., Uchida, K., Chambers, J. and Shii, H. (2021). Long-term postsurgical outcomes of mast cell tumors resected with a margin proportional to the tumor diameter in 23 dogs. Journal of Veterinary Medical Science. 83(2), 230–233. DOI: https://doi.org/10.1292/jvms.20-0281
5. Milovancev, M., Townsend, K., Tuohy, J., Gorman, E., Bracha, S., Curran, K. and Russell, D. (2019). Long‐term outcomes of dogs undergoing surgical resection of mast cell tumors and soft tissue sarcomas: A prospective 2‐year‐long study. Veterinary Surgery. 49(1), 96–105. DOI: https://doi.org/10.1111/vsu.13225
6. Monteiro, B., Boston, S. & Monteith, G. (2011). Factors influencing complete tumor excision of mast cell tumors and soft tissue sarcomas: a retrospective study in 100 dogs. Canadian Veterinary Journal. 52(11), 1209–1214.
7. Pratschke, K., Atherton, M., Sillito, J. & Lamm, C. (2013). Evaluation of a modified proportional margins approach for surgical resection of mast cell tumors in dogs: 40 cases (2008–2012). Journal of the American Veterinary Medical Association. 243(10), 1436–1441. DOI: https://doi.org/10.2460/javma.243.10.1436
8. Saunders, H., Thomson, M., O'Connell, K., Bridges, J. & Chau, L. (2020). Evaluation of a modified proportional margin approach for complete surgical excision of canine cutaneous mast cell tumours and its association with clinical outcome. Veterinary and Comparative Oncology. 19(4). DOI: https://doi.org/10.1111/vco.12630
9. Seguin, B., Leibman, N., Bregazzi, V., Ogilvie, G., Powers, B., Dernell, W., Fettman, M. & Withrow, S. (2001). Clinical outcome of dogs with grade-II mast cell tumors treated with surgery alone: 55 cases (1996–1999). Journal of the American Veterinary Medical Association. 218(7), 1120–1123. DOI: https://doi.org/10.2460/javma.2001.218.1120
10. Sfiligoi, G., Rassnick, K., Scarlett, J., Northrup, N. & Gieger, T. (2005). Outcome of dogs with mast cell tumors in the inguinal or perineal region versus other cutaneous locations: 124 cases (1990–2001). Journal of the American Veterinary Medical Association. 226(8), 1368–1374. DOI: https://doi.org/10.2460/javma.2005.226.1368
11. Simpson, A., Ludwig, L., Newman, S., Bergman, P., Hottinger, H. and Patnaik, A. (2004). Evaluation of surgical margins required for complete excision of cutaneous mast cell tumors in dogs. Journal of the American Veterinary Medical Association. 224(2), 236–240. DOI: https://doi.org/10.2460/javma.2004.224.236