What are the recommended definitive margins for excision of primary melanoma?

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Background

Surgery is currently the only potentially curative treatment for primary cutaneous melanoma. Standard treatment is wide local excision (WLE) of the skin and subcutaneous tissues around the melanoma with a safety margin. . The aim is complete excision of all in situ and invasive melanoma components. The purpose of the excision margin of additional tissue is to remove both the primary tumour and any melanoma cells that might have spread from the primary melanoma into the surrounding skin and subcutaneous tissue. If the malignant cells have spread no further, and are entirely included in the wider excision margin, the operation should prove to be curative.

Complete excision should be confirmed by histological examination of the excised specimen with special reference to the periphery. When present, the in-situ component (which may not be apparent macroscopically), often extends beyond the invasive melanoma, and complete excision of both is mandatory.

The width of excision margins is important because there could be trade-off between a better cosmetic result and poorer long-term outcomes if margins become too narrow.

The recommendations for the width of melanoma excision margins are based on the Breslow thickness of the primary melanoma at its thickest depth of invasion, as determined by histological assessment of the initial excision biopsy. In general, wider excision is favoured for tumours with a less favourable prognosis, such as increased Breslow thickness.

Surgical excision margins according to the tumour thickness have been assessed in six randomised controlled trials (RCTs) including a total of 4233 patients.[1][2][3][4][5][6] All six RCTs assess width of excision but do not consider depth of excision. These RCTs compare narrow (1 to 2 cm) versus wide (3 to 5 cm) excision margins and assess outcomes including overall survival, melanoma specific survival and ‘local recurrence’, with median follow-up ranging from 5 to 16 years. However, no RCT has yet addressed the most important question of 1cm vs 2cm surgical margins for intermediate thickness (≥ 1mm to 4mm) and thick (> 4mm) melanomas in terms of clinical outcome (recurrence and survival) which is what is required to answer the question of whether 1cm margins are adequate and safe for treatment of all melanoma Breslow thicknesses. In addition, definitions of ‘local recurrence’ are often inconsistent or unstated, and the impact on patient survival is unclear, so ‘local recurrence’ data must be interpreted with caution. True local recurrence is development of melanoma associated with the scar.</span> In addition, the RCTs have been further assessed in six systematic reviews and meta-analyses where a primary melanoma has been previously excised.[7][8][9][10][11][12] Re-occurrence" of melanoma close to but away from the previous primary melanoma excision scar typically represents lymphatic metastasis also termed "local satellitosis". These different situations have been often combined inappropriately as "local recurrence". There are also several published case series addressing excision margins that provide further data. Unfortunately, the extent of surgical excision margins that should be used for a given thickness of melanoma and the magnitude of benefit of different margins remains unclear because the trials use different criteria other than 1 vs 2 cm margins to directly compare invasive melanomas.

There are no RCTs which assess depth of excision. Recent studies suggest that excision of the deep fascia does not improve the outcome of melanomas thicker than 1 mm[13] or 2 mm[14] but results of these retrospective studies must be interpreted with caution because accurate data collection is often difficult. The depth of excision in usual clinical practice is excision down to but not including the deep fascia, unless the fascia is involved with tumour or is technically warranted.

However, in case of thick lesions, in the absence of a sufficient subcutis layer and 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. Similarly, 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.

Acral lentiginous and subungual melanomas are specific types of cutaneous melanoma that arise in the extremities/soles/palms and nail matrix respectively. Treatment of these melanomas for the most part has not been assessed in trials to assist in decision making. Case series data offers the best quality data currently to help guide treatment approaches.

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Economic outcomes, patient preferences and adverse events

The available RCTs, systematic reviews and meta-analyses do not assess economic outcomes and patient preferences regarding width of excision. The Cochrane review does however state, “From the individual’s point of view, when faced with a diagnosis of melanoma, the most important consideration is to make sure that it is removed with as much certainty as possible so that it is all gone! The size and depth of the excision should therefore err on the side of safety first. However, quality of life after surgery is an important consideration and unnecessary disfigurement should be avoided.” An optimal safe balance is therefore is desirable to achieve survival and quality of life.

However, three trials, the Intergroup,[1] the UKMSG[6] and the 1992 Swedish Study,[4] do report adverse event outcome measures.[insert citations here]

The Intergroup trial[1] assessed skin grafting, hospital stay, wound infection rate, wound dehiscence (skin separation) rates:

  • The rate of skin grafts was reduced from 46% with 4 cm surgical margins to 11% with 2 cm surgical margins (P < 0.001).
  • For the study cohort as a whole, the hospital stay was reduced from 7.0 days for participants receiving 4 cm surgical margins to 5.2 days for those receiving 2 cm margins (P = 0.0001). This reduction in length of hospital admission was mainly due to the reduced need for skin grafting, since the hospital stay for those who had a skin graft was 3.5 days longer than that for those who had a primary wound closure (6.5 days versus 3.0, P < 0.01).
  • There was no significant difference between wound infection rates (4.6% and 5.4%) between the two groups (4 and 2 cm margins respectively).
  • There was no significant difference between wound dehiscence rates (4.2% and 4.6%) between the two groups (4 and 2 cm margins respectively).

The UKMSG trial[6] stated that the rate of surgical complications was 7.8% among participants with a 1 cm excision margin compared with 13.9% among those with a 3 cm excision margin (P = 0.05).

The 1992 Swedish Study[4] summarised their rates of primary closures, graft and flap between the two groups. Primary closure of the wound was possible in 319 patients (69%) in the 2-cm group compared with 173 (37%) in the 4-cm group. Split skin graft was used in 58 patients (12%) and 223 (47%), in the narrow and wide excision groups respectively. A surgical flap was used in 19 patients (4%) in the narrow excision group and 27 (6%) in the wide excision group.

These data reflect practices at the times that the studies were conducted, using wide excision margins (4-5cm margins). With the narrower margins used in current practices (1-2cm) these outcome data, such as lengths of hospital stay, may be different.

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See the following sections:

References

  1. 1.0 1.1 1.2 Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 2001 Mar 1;8(2):101-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11258773.
  2. 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.
  3. 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.
  4. 4.0 4.1 4.2 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.
  5. 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.
  6. 6.0 6.1 6.2 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.
  7. 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.
  8. 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.
  9. Lens MB, Nathan P, Bataille V. Excision margins for primary cutaneous melanoma: updated pooled analysis of randomized controlled trials. Arch Surg 2007 Sep;142(9):885-91; discussion 891-3 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17875844.
  10. 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.
  11. 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.
  12. 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.
  13. Grotz TE, Glorioso JM, Pockaj BA, Harmsen WS, Jakub JW. Preservation of the deep muscular fascia and locoregional control in melanoma. Surgery 2013 Apr;153(4):535-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23218886.
  14. 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.

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Appendices