Excision margins for invasive melanoma and melanomas at other sites

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Melanomas ≤ 1mm thick

There are no RCTs that specifically assess only melanomas less than 1 mm thick. However, three of the RCTs that assessed melanomas ≤ 2mm thick included 762 participants with melanomas ≤ 1mm thick. These were the French trial (159 participants),[1] 1982 Swedish trial (244 participants)[2] and the World Health Organisation (WHO) trial (359 participants).[3] No difference in mortality was found for wider excision (5 cm in the French study,[1] 5 cm in the 1982 Swedish study,[2] 3 cm in the WHO study[3]) compared with narrower excision (2 cm in the French study,[1] 2 cm in the 1982 Swedish study,[2] 1 cm in the WHO study[3]). Of note, only 185 participants (WHO trial[3]) were treated with a 1 cm excision margin.

A recently published case-control study of 11,290 patients with thin melanomas (≤ 1 mm thick) showed that local recurrence was associated with < 8 mm histologic excision margins (corresponding to < 1 cm margins in vivo), suggesting that a ≥ 1 cm clinical excision margin for thin melanomas reduces the risk of local recurrence.[4]

Therefore, there is only limited data on which to base clinical recommendations for excision margins for melanoma ≤ 1mm thick. However, a 1 cm margin is widely accepted as standard treatment for thin (< 1 mm) melanomas and most international guidelines recommend 1 cm excision margins for melanoma < 1 mm thick.

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Melanomas 1.01 mm–2.00 mm thick

Four RCTs assessed melanomas between 1 mm and 2 mm thick and included 1429 patients. These were the French trial (167 participants),[1] the 1982 Swedish trial (745 participants),[2] the WHO trial (245 participants)[3] and the Intergroup trial (272 participants).[5] None of these trials demonstrated a statistically significant difference in overall survival between the two groups that were treated with wide (5 cm in the French study,[1] 5 cm in the 1982 Swedish study,[2] 3 cm in the WHO study,[3] 4 cm in Intergroup study[5]) or narrow (2 cm in the French study,[1] 2 cm in the 1982 Swedish study,[2] 1 cm in the WHO study,[3] 2 cm in the Intergroup study[5]) excision. Of note, only 113 participants (WHO trial[3]) were treated with a 1 cm excision margin.

Three retrospective studies[6][7][8] have assessed the width of excision margins for melanomas ≤ 2 mm thick, but the magnitude of any potential associations is difficult to understand, due to the need for multivariate adjustment for confounding by other risk factors. A large single centre retrospective study of 2681 patients with melanoma ≤ 2 mm thick suggested that a 1 cm clinical margin was adequate for cutaneous melanomas ≤ 2 mm in thickness and does not impact local recurrence or survival.[6] In another large single centre retrospective study of 2131 patients with primary cutaneous melanomas 1.01-2.00 mm thick, pathologic excision margins of < 8 mm were associated with worse regional node recurrence-free survival and distant recurrence-free survival compared with margins ≥ 8 mm (corresponding to ≥ 1 cm surgical margins), but did not translate into a statistically significant difference in melanoma-specific survival.[7] In another retrospective single centre series of 576 patients with 1-2 mm thick melanomas, 1 cm margins were associated with a small increase in local recurrence compared with 2 cm margins but this did not impact on overall survival.[8]

Again, there are only limited data on which to base clinical recommendations for excision margins for melanoma 1.01 mm–2.00 mm thick. There is little data to help differentiate between the clinical outcomes (local recurrence and survival) for 1 cm and 2 cm excision margins for these tumours. Most international guidelines recommend either 1 cm excision margins or 1–2 cm excision margins for 1.01 mm–2.00 mm melanoma.

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Melanomas 2.01 mm–4.00 mm thick

Three RCTs included participants who had melanomas between 2 and 4 mm thick and included 1516 patients. These were the Intergroup trial (190 participants),[5] the 1992 Swedish trial (666 participants)[9] and the United Kingdom Melanoma Study Group (UKMSG) trial (approximately 660 participants).[10] None of these trials demonstrated a statistically significant difference in overall survival between the two groups who were treated with wide (4 cm in the Intergroup study,[5] 4 cm in the 1992 Swedish study,[9] 3 cm in UKMSG study[10]) or narrow (2 cm in the Intergroup study,[5] 2 cm in the 1992 Swedish study,[9] 1 cm in UKMSG study[10]) excision.

The UKMSG trial "found a greater risk of locoregional recurrence when melanomas that were at least 2 mm thick were excised with a 1-cm margin, rather than a 3-cm margin (hazard ratio 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05)”. However, it should be noted that this combined outcome measure of locoregional recurrence was defined only after the trial had been commenced (that it, locoregional recurrence was not predefined in the study protocol).

The recently updated UKMSG trialshowed a statistically significant improvement in melanoma specific survival (MSS) in favour of wide excision compared with narrow excision (HR 1.24: 95% CI 1.01 – 1.53; p = 0.041) but no statistically significant difference in overall survival between the 2 groups (hazard ratio [HR] 1.14, 95% CI 0.96 – 1.36; p = 0.14).[10] It is difficult to interpret the implications of this modest improvement in melanoma specific survival in the absence of any significant difference in overall survival. Of note, melanoma specific survival and overall survival were both secondary outcomes in this study. Melanoma specific survival is more difficult than overall survival to measure accurately because it relies on accurate information about cause of death. A significant number of melanomas in the UKMSG study were thick melanomas over 4 mm, which may have influenced the overall study results. In an accompanying editorial, it is suggested that “the excess nodal disease in the narrow margin group was indicative of poor prognostic disease before the intervention, rather than resulting from the narrow margin intervention itself” which might be an explanation of the significant difference in locoregional recurrence. It should also be noted that sentinel node biopsy was not used in the UKMSG trial and it is not known how this might have altered locoregional recurrence and the survival outcome in that study.

In a large single centre retrospective review of 1587 patients with melanomas 2.01 mm–4.00 mm thick, a histopathologic excision margin of 8 mm or more (roughly equivalent to a ≥ 1 cm surgical margin) was associated with increased local and intransit recurrence-free survival and disease-free survival compared with a less than 8 mm margin.[11] Another retrospective single centre cohort study of 325 patients with melanoma > 2 mm thick evaluating 1 cm or 2 cm excision margins showed no significant differences in locoregional and distant metastasis, and disease-free and overall survival between the groups.[12]

Given there is no difference in overall survival when comparing 4 cm and 2 cm margins in the Intergroup study[5] and 1992 Swedish study,[9] it seems reasonable to conclude that in most cases there is no need to take more than 2 cm margins for thick melanomas. Indeed, there is no convincing RCT evidence that a margin greater than 2 cm offers additional benefit for the patient in terms of overall survival or ‘local recurrence’, irrespective of melanoma thickness. The clinical significance of the modest improvement in melanoma specific survival in the UKMSG trial[10] in the 3 cm excision group compared with the 1 cm excision group in the absence of benefit in overall survival remains unclear. On balance, given the available evidence, we continue to recommend 1-2 cm excision margins for melanomas of Breslow thickness 2-4 mm until more robust data is available. This is unchanged from our 2008 recommendation. However, we recognise that in certain areas of the body (eg face) and in the frail, excision margins greater than 1cm may not be possible.

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Melanomas > 4 mm thick

Approximately 240 participants in the UKMSG study had melanomas > 4 mm thick.[10] A further 270 participants in the 1992 Swedish Study had melanomas 4 mm or thicker.[9] In both of these studies there was no statistically significant difference in overall survival between the two groups who were treated with wide or narrow excision.[10][9] Within these two studies patients with melanomas > 4 mm were analysed as part of the entire cohort and not as separate groups so it is not known how well the overall results can be extrapolated to these thicker melanomas.[10][9]

In a retrospective study of 632 clinically lymph node negative patients with melanomas more than 4 mm thick, histopathologically determined primary tumour excision margins more than 16 mm (corresponding to 2 cm surgical margins) were associated with better local control compared with narrower margins.[13]

No RCT data exist to show that any margin wider than 2 cm (that is 3, 4, or 5 cm) would result in any superior disease-specific outcomes, but these wider margins are associated with increased surgical morbidity. Most international guidelines suggest an excision margin of 2 cm for thick tumours over 4 mm thick. Individual adverse prognostic melanoma characteristics may dictate more caution and wider excision margins as clinically appropriate, although RCT data is lacking.

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Melanomas at other sites

The six RCTs[5][3][2][9][1][10] included in our review do not adequately address the issues of melanomas in specific body sites, such as head and neck, distal extremities, hands and feet (including digits and subungual melanomas). For example, only the French study included melanomas on the head and neck and this involved only 16 participants.[1]

In special areas where the deep fascia is less clearly defined, such as the face, neck and breast, the vertical excision margins require adaptation to the anatomic condition, for example down to the perichondrium on the ear.

The morbidity (particularly 'cost' for reconstruction, complications or potential disfigurement) associated with wider excisions on the face is likely to be greater than for those on the trunk. For example, even 1 cm margins are potentially problematic in critical facial locations. A few non-randomised trials suggest that excision margins on the head and neck can be safely reduced but the results must be interpreted with caution given the nature of the studies. There are no RCT data that demonstrate whether narrower excision margins impact on mortality or recurrence rates in head and neck melanoma.

In a recently published study, 79 cases of primary, invasive head and neck melanoma were treated by wide local excision and followed prospectively for local recurrence.[14] Forty-two wide local excisions were performed according to current National Comprehensive Cancer Network (NCCN) practice guidelines and reduced margins were utilized in 37 cases to preserve critical anatomical structures such as the eyelid, nose, mouth and auricle. Reducing margins of wide local excision did not increase local recurrence rates as demonstrated by local recurrence-free survival (90.4% vs. 91.9%, P = 0.806) at 5 years follow-up, suggesting that excision margins may be safely reduced in melanomas in close proximity to structures of the head and neck, but this was a small non-randomised study.

In a retrospective study of 368 melanomas of the face, the authors suggest that reduced excision margins can be employed in melanomas of the face.[15]

A prospective study evaluated 161 patients with melanoma of the external ear. The median thickness of the tumours in the present study was 1.08 mm (mean 1.51 mm; range 0.18–8.50 mm), and the median excision margins were 11.0 mm (mean 12.61 mm; range 2.0–31.0 mm). The 3-year disease-specific survival rate was 98%, and the 3-year recurrence-free survival rate was 83%. The authors concluded that the use of micrographic surgery, made it possible to reduce the excision margins (median 5 mm vs. 10 mm) without an increased risk of recurrence.[16]

A retrospective chart review of 78 patients evaluated the prognostic variables and clinical ramifications of melanoma of the ear.[17] Melanoma thickness averaged 1.7 mm (range 0.2–7.0 mm). After a mean follow-up of 55.7 months, 10 patients (13%) had local recurrence, 9 patients (12%) had regional recurrence, and systemic metastases had developed in 17 patients (22%). The authors concluded that treatment of malignant melanoma of the external ear should follow current standard guidelines, which require wide local excision with negative margins.

Guidelines for wide excision of cutaneous melanomas according to Breslow thickness are impractical when considering melanomas arising on eyelid skin. A retrospective study of 56 patients with invasive cutaneous eyelid melanoma sought to determine whether excision margins influenced locoregional recurrence, and to identify prognostic factors for survival in these patients.[18] Local recurrence occurred in 12 patients (21%), nodal metastasis in 6 (11%) and distant metastasis in 2 (4%). Pathological margins > 2 mm from the in situ component of the tumour were associated with increased disease-free survival (P = 0.029) compared with margins ≤2 mm but there was no statistically significant benefit for a pathological margin > 2 mm from the invasive component. The results suggest that, as a minimum, an in vivo surgical margin of 3 mm (corresponding approximately to a 2 mm pathological margin after tissue fixation) is desirable for eyelid melanomas. The authors recommended a surgical excision margin of 3 mm for eyelid melanomas ≤ 1 mm in Breslow thickness but for melanomas > 1 mm in thickness, the current practice of aiming to achieve 5 mm margins would seem reasonable. Patients with lower eyelid melanomas warrant particularly close follow-up given their higher local recurrence rate.

Management of digital melanomas including the subset of subungual melanomas often includes partial amputation.[19][20] As with facial lesions, there are no RCTs available to help determine whether less aggressive surgery would be as effective. Management involves achieving a balance between adequate melanoma excision with the most appropriate margins for the site and characteristics of the melanoma, while maintaining the optimal preservation of function.

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Evidence summary and recommendations

Evidence summary Level References
There is no convincing RCT evidence that a margin greater than 2cm offers additional benefit for the patient in terms of overall survival or ‘local recurrence’, irrespective of melanoma thickness. I, II [5], [3], [2], [9], [1], [10], [21], [22], [23], [24], [25], [26]
Furthermore, two RCTs show evidence that a margin greater than 1cm offers no survival advantage, although it is not clear whether a wider margin reduces the risk of ‘local recurrence’. II [3], [27]
Systematic review indicates that there are currently inadequate data to confirm a mortality difference between wider and narrower excision for primary invasive melanoma. I [21], [22], [23], [24], [25], [26]
For acral lentiginous and subungual melanomas there are no RCTs or systematic reviews to define excision margins. Data are from retrospective case studies. There is limited RCT data for head and neck melanoma with the majority of data also derived from retrospective case series.

Excision margins might be modified to accommodate individual anatomic sites or functional considerations, but this practice would be based solely on case-series information, and individual factors, rather than RCT evidence which is currently lacking.

III-2, IV [14], [15], [17], [18], [19], [20]

Recommendations

Evidence-based recommendationQuestion mark transparent.png Grade
(pT1) melanoma < 1.0 mm
After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.
B


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Evidence-based recommendationQuestion mark transparent.png Grade
(pT2) melanoma 1.01 mm–2.00 mm
After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1–2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.
B


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Evidence-based recommendationQuestion mark transparent.png Grade
(pT3) melanoma 2.01 mm–4.00 mm
After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 1–2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.

Caution should be exercised for melanomas 2.01–4.00 mm thick, especially with adverse prognostic factors, because evidence concerning optimal excision margins is unclear. Where possible, it may be desirable to take a wider margin (2 cm) for these tumours depending on the tumour site and characteristics, and prevailing surgeon/patient preferences.

B


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Evidence-based recommendationQuestion mark transparent.png Grade
(pT4) melanoma > 4.0 mm
After initial excision biopsy, the radial excision margins, measured clinically from the edge of the melanoma, should be 2 cm. Minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary; positive histological margins are unacceptable.
B


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Evidence-based recommendationQuestion mark transparent.png Grade
Acral lentiginous and subungual melanoma are usually treated with a minimum margin as set out above, where practicable, including partial digital amputation usually incorporating the joint immediately proximal to the melanoma.
D


Evidence-based recommendationQuestion mark transparent.png Grade
Excision margins might be modified to accommodate individual anatomic sites or functional considerations, but this practice would be based solely on case-series information, and individual factors, rather than RCT evidence which is currently lacking.
D


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Practice pointQuestion mark transparent.png

Excisions should have vertical edges to ensure consistent margins.


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For all melanomas, minimum clearances from all margins should be stated/assessed. Consideration should be given to further excision if necessary because positive histological margins are unacceptable.


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Excision biopsy of the complete lesion with a narrow (2mm) margin is appropriate for the definitive diagnosis of primary melanoma. Once the diagnosis of melanoma has been made, re-excision of the lesion (biopsy site) should then be performed in order to achieve the definitive, wider margins that are recommended in these guidelines.


Practice pointQuestion mark transparent.png

Depth of excision in usual clinical practice is excision down to but not including the deep fascia unless it is involved or has been reached during the diagnostic excision. For body sites where there is particularly deep subcutis, it is usual practice to excise to a depth equal to the recommended lateral (radial) excision margins for that specific melanoma; in these cases it is not deemed necessary to excise right down to fascia.


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Where tissue flexibility is limited, a flap repair or skin graft is often necessary subsequent to an adequate margin of removal.


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Most primary melanomas can be treated as an outpatient under local anaesthesia or as a day-case.


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Patients should be informed that surgical excision may be followed by wound infection, bleeding, haematoma, failure of the skin graft or flap, risk of numbness, a non-cosmetic scar, dehiscence and the possibility of further surgery.


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Some tumours may be incompletely excised despite using the above-recommended margins. These include melanomas occurring in severely sun-damaged skin (e.g. lentigo maligna) and those with difficult-to-define margins (e.g. amelanotic and desmoplastic melanomas). In these categories, the presence of atypical melanocytes at the margins of excision should be detected by comprehensive histological examination (including immunohistochemical staining) and followed by wider excision.


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Amelanotic melanoma can present significant difficulties for defining a margin with up to one third of subungual and nodular melanomas being non-pigmented. This may dictate choice of a wider margin, or further re-excision, where practicable.


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For patients with deeper invasive melanomas (> 1 mm thick), referral to a specialised melanoma centre or discussion in a multidisciplinary meeting should be considered to ensure that best practice is implemented and for the collection of national outcome data. This may present logistic difficulties in regional and remote areas, but input from a specialist melanoma centre.

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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Khayat D, Rixe O, Martin G, Soubrane C, Banzet M, et al. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer 2003 Apr 15;97(8):1941-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12673721.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Cohn-Cedermark G, Rutqvist LE, Andersson R, Breivald M, Ingvar C, Johansson H, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 2000 Oct 1;89(7):1495-501 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11013363.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Cascinelli N. Margin of resection in the management of primary melanoma. Semin Surg Oncol 1998 Jun;14(4):272-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9588719.
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  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 Gillgren P, Drzewiecki KT, Niin M, Gullestad HP, Hellborg H, Månsson-Brahme E, et al. 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial. Lancet 2011 Nov 5;378(9803):1635-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22027547.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 Hayes A, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, et al. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. The Lancet Oncology 2016 Jan 11 [cited 2016 Jan 18] Abstract available at http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00482-9/abstract.
  11. Lamboo LG, Haydu LE, Scolyer RA, Quinn MJ, Saw RP, Shannon KF, et al. The optimum excision margin and regional node management for primary cutaneous T3 melanomas (2-4 mm in Thickness): a retrospective study of 1587 patients treated at a single center. Ann Surg 2014 Dec;260(6):1095-102 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25072430.
  12. Hunger RE, Seyed Jafari SM, Angermeier S, Shafighi M. Excision of fascia in melanoma thicker than 2 mm: no evidence for improved clinical outcome. Br J Dermatol 2014 Dec;171(6):1391-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25392906.
  13. Pasquali S, Haydu LE, Scolyer RA, Winstanley JB, Spillane AJ, Quinn MJ, et al. The importance of adequate primary tumor excision margins and sentinel node biopsy in achieving optimal locoregional control for patients with thick primary melanomas. Ann Surg 2013 Jul;258(1):152-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23426339.
  14. 14.0 14.1 Rawlani R, Rawlani V, Qureshi HA, Kim JY, Wayne JD. Reducing margins of wide local excision in head and neck melanoma for function and cosmesis: 5-year local recurrence-free survival. J Surg Oncol 2015 Jun;111(7):795-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25712156.
  15. 15.0 15.1 Möhrle M, Schippert W, Garbe C, Rassner G, Röcken M, Breuninger H. [Prognostic parameters and surgical strategies for facial melanomas]. J Dtsch Dermatol Ges 2003 Jun;1(6):457-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16295139.
  16. Jahn V, Breuninger H, Garbe C, Moehrle M. Melanoma of the ear: prognostic factors and surgical strategies. Br J Dermatol 2006 Feb;154(2):310-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16433802.
  17. 17.0 17.1 Pockaj BA, Jaroszewski DE, DiCaudo DJ, Hentz JG, Buchel EW, Gray RJ, et al. Changing surgical therapy for melanoma of the external ear. Ann Surg Oncol 2003 Jul;10(6):689-96 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12839855.
  18. 18.0 18.1 Harish V, Bond JS, Scolyer RA, Haydu LE, Saw RP, Quinn MJ, et al. Margins of excision and prognostic factors for cutaneous eyelid melanomas. J Plast Reconstr Aesthet Surg 2013 Aug;66(8):1066-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23688975.
  19. 19.0 19.1 Furukawa H, Tsutsumida A, Yamamoto Y, Sasaki S, Sekido M, Fujimori H, et al. Melanoma of thumb: retrospective study for amputation levels, surgical margin and reconstruction. J Plast Reconstr Aesthet Surg 2007;60(1):24-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17126263.
  20. 20.0 20.1 Cohen T, Busam KJ, Patel A, Brady MS. Subungual melanoma: management considerations. Am J Surg 2008 Feb;195(2):244-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18086464.
  21. 21.0 21.1 Haigh PI, DiFronzo LA, McCready DR. Optimal excision margins for primary cutaneous melanoma: a systematic review and meta-analysis. Can J Surg 2003 Dec;46(6):419-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14680348.
  22. 22.0 22.1 Lens MB, Dawes M, Goodacre T, Bishop JA. Excision margins in the treatment of primary cutaneous melanoma: a systematic review of randomized controlled trials comparing narrow vs wide excision. Arch Surg 2002 Oct;137(10):1101-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12361412.
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  24. 24.0 24.1 Mocellin S, Pasquali S, Nitti D. The impact of surgery on survival of patients with cutaneous melanoma: revisiting the role of primary tumor excision margins. Ann Surg 2011 Feb;253(2):238-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21173691.
  25. 25.0 25.1 Wheatley K, Wilson J, Gaunt P, Marsden J. Are narrow surgical excision margins for primary cutaneous melanoma safe? An updated systematic review and meta-analysis. JDDG 2013;(Suppl 7):1-23.
  26. 26.0 26.1 Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev 2009 Oct 7;(4):CD004835 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19821334.
  27. Hayes AJ, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, et al. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol 2016 Feb;17(2):184-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26790922.

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Appendices