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Surgical Excision of Melanoma
Key Points
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Surgical excision is the cornerstone for the initial management of primary melanoma.
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The major focus of surgical excision for melanoma is to remove the primary tumor and any local disease.
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The initial treatment for melanoma should include excision with 5 mm margins (for in-situ lesions), 1 cm margins (for tumors 0.01–1.00 mm of invasion), 1–2 cm margins (for tumors 1.01–2.00 mm of invasion), 2 cm margins for tumors greater than 2 mm invasion and depth to fascia with consideration for sentinel lymph node biopsy if appropriate criteria are met.
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Closure techniques are varied as a function of excision size and anatomic sites.
Introduction
Surgical excision remains the main treatment modality for patients with primary cutaneous melanoma. The main goal of surgical excision is to remove all melanoma tumor cells at the primary melanoma site in order to provide the best oncological outcome that minimizes the risk of local recurrence. The surgical excision should also be carried out in such a manner as to minimize functional impairment and cosmetic disfigurement. The appropriate width of surgical resection has been a longstanding controversy. Traditionally, many institutions have promoted wide local excisions of melanomas with margins of 3 to 5 cm. Most of these recommendations were not based on scientific data but rather on anecdotal evidence that patients treated with wider excisions experienced lower likelihood of recurrence at the resection site. Well-conducted randomized clinical trials have now resolved many of these excision margin controversies, and this chapter will highlight the current recommendations for excision of primary cutaneous melanoma.
History
William Norris in 1857 first reported on the need for a wide excision of primary melanoma with surrounding normal tissue after he observed a local recurrence of melanoma with extensive tumor dissemination after an initial excision with minimal margins. In 1907, W. Sampson Handley observed histological evidence of ‘centripetal lymphatic spread’ in an autopsy of a patient with a locally advanced melanoma. Based on this somewhat minimal information, he recommended an even more aggressive excision with 2 inches (5 cm) of normal skin surrounding the primary melanoma with concomitant excision of the underlying subcutaneous tissue down to the muscle fascia and a regional lymph node dissection. These findings formed the basis for a recommendation of extensive margin resection of primary melanoma over the following 60 years. The recommendation was based on the belief that undertreatment of the patient with a narrow excision increased the risk of local recurrence and distant metastatic spread. It was not until the 1970s that the need for such an extensive margin excision was questioned.
In 1977 Breslow and Macht investigated the incidence of local recurrence in 62 patients with melanomas of 0.76 mm or less in thickness treated with 0.1 cm to 5.5 cm excision margins. Of the 62 patients, 20 underwent excisions with margins of 1.0 cm or less. None of the 62 patients developed a local recurrence or metastatic disease. This study and other studies established that local recurrence and metastatic disease rates were primarily governed by the melanoma thickness and biology of disease, and less by the margins of excision. The Breslow thickness subsequently became an important stratification criterion for randomized clinical trials evaluating different excision margins.
Excision margin trials
Prior to the 1970s, no randomized trials had been conducted evaluating the safety of narrow margin excisions. Based on the findings of Breslow and Macht, several large randomized clinical trials have been conducted evaluating the safety of narrow margin excision. These trials have tested the following paradigms: 1) local failure is a function of both biology of the primary tumor and extent of excision; 2) narrow (1 cm) margins are safe in thin melanomas with a low risk of recurrence; 3) wider excisions lower the risk of local and/or regional recurrences in thicker and/or ulcerated melanomas; 4) increased rates of local/regional failure may or may not have an impact on survival.
To date, five large prospective randomized clinical trials, published in 11 reports, have evaluated the excision margins and the impact of these on the risk of local recurrence and survival ( Table 49.1 ). All of these randomized clinical trials were multicenter and four were multinational. In all of them, the surgical excision margins was measured clinically and no specific correlation between clinical margins and histological margins was given. Two of the trials compared 1 to 3 cm excision margins (World Health Organization [WHO] Melanoma Program Trial No. 10, and the United Kingdom Melanoma Study Group Trial ), one compared 2 to 4 cm excision margins (the Intergroup Melanoma Surgical Trial ) and two compared 2 to 5 cm margins (the French Cooperative Group Trial and the Swedish Melanoma Group Trial ).
Table 49.1
Prospective Randomized Trials Assessing Surgical Excision Margins for Primary Cutaneous Melanoma
| Randomized Surgical Trial | N | Tumor Thickness (mm) | Surgical Excision (cm) | Median Follow-up (Years) | |
|---|---|---|---|---|---|
| Narrow | Wide | ||||
| WHO Melanoma Group Trial No. 10 | 612 | ≤2 | 1 | ≥3 | 15 |
| French Group of Research on Malignant Melanoma Trial | 337 | <2.1 | 2 | 5 | 16 |
| Swedish Melanoma Trial Group | 989 | >0.8, ≤2 | 2 | 5 | 11 (survival) 8 (recurrence) |
| Intergroup Melanoma Surgical Trial | 468 | 1–4 | 2 | 4 | 10 |
| UK Melanoma Study Group | 900 | ≥2 | 1 | 3 | 5 |
The French Cooperative Group Trial (melanomas ≤ 2mm, margins 2 vs 5 cm)
The French Cooperative Group Trial, conducted by the French Group of Research on Malignant Melanoma, was initiated in 1981 and randomized 337 patients with cutaneous melanomas ≤2 mm (in the later publication this was referred to as <2.1 mm) in Breslow thickness on the trunk, limbs, head and neck to either 2 cm or 5 cm excision margins. Patients with melanomas on the fingers, toes and nails were excluded from the study. The results of the study were reported initially in 1993 in abstract format and published in 2003. After a median follow-up of 16 years (192 months), 55 (16.8%) patients developed recurrent disease; 22 (13.6%) of these underwent a 2 cm excision and 33 (20%) underwent a 5 cm excision. This difference was not statistically significant, P =0.22. The majority of recurrences were in regional lymph nodes and distant sites, whereas the local recurrence rate was very low in both of the randomized groups. A total of five patients developed a local recurrence, one (0.6%) in the 2-cm group and four (2.4%) in the 5-cm group. This difference was not statistically different. There were no significant differences in the 10-year disease-free survival rates (85% vs 83% for the 2-cm and 5-cm groups, respectively) and the 10-year overall survival rates (87% vs 86%) ( Table 49.2 ). Based on this, the authors concluded that in patients with cutaneous melanomas ≤ 2 mm, a 2 cm excision margin is sufficient, and a traditional 5 cm margin is not necessary.
Table 49.2
Actuarial Rates of Overall Survival, Disease-Free Survival, and Recurrence in Prospective Randomized Trials Assessing Surgical Excision Margins for Primary Cutaneous Melanoma
| Randomized Surgical Trial | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Category | French Cooperative Group Trial | WHO Melanoma Group Trial No. 10 | Swedish Melanoma Trial Group | Intergroup Melanoma Surgical Trial | UK Melanoma Study Group | ||||||||||
| Breslow thickness | ≤2 mm | ≤2 mm | >0.8–2 mm | 1–4 mm | ≥2 mm | ||||||||||
| Margins | Margins | Margins | Margins | Margins | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 cm | 5 cm | P | 1 cm | 3 cm | P | 2 cm | 5 cm | P | 2 cm | 4 cm | P | 1 cm | 3 cm | P | |
| Disease-Free Survival | |||||||||||||||
| 5-year | – | – | – | – | 81% | 83% | NS | 75% | 80% | NS | 51% | 56% | 0.06 | ||
| 10-year | 85% | 83% | NS | 82% * | 84% * | NS | 71% | 70% | NS | – | – | – | – | ||
| Overall Survival | |||||||||||||||
| 5-year | 93% | 90% | NS | 97% † | 96% † | NS | 86% | 89% | NS | 76% | 82% | NS | 68% | 69% | NS |
| 10-year | 87% | 86% | NS | 90% * 87% ‡ | 90% * 85% ‡ | NS NS | 79% | 76% | NS | 70% | 77% | 0.074 | – | – | |
| Local recurrence as first relapse | – | – | 2.6% ‡ | 1.0% ‡ | NS | 0.2% * | 1.0% * | NS | 0.4% | 0.9% | NS | 3.3% | 2.9% | NS | |
| Local recurrence at any time | 0.6% | 2.4% | NS | – | – | 0.6% * | 1.0% * | NS | 2.1% | 2.6% | NS | – | – | ||
| Locoregional recurrence | 8.7% | 9.1% | NS | 8.9% * | 8.5% * | NS | 19.3% * | 14.8% * | 0.06 | – | – | 37.1% | 31.8% | 0.05 | |
| Overall recurrence | 13.6% | 20% | NS | 14.4% * | 13.0% * | NS | 21% * | 19% * | NS | – | – | 45.5% | 38.5% | 0.03 | |
–, not reported; NS, not significant; WHO, World Health Organization; UK, United Kingdom.
WHO Melanoma Program Trial No. 10 (melanomas ≤2 mm, margins 1 vs 3 cm)
The WHO Melanoma Program initiated a wide-excision randomized clinical trial at the same time as the French group and between 1980 and 1985 randomized 703 patients with primary cutaneous melanomas ≤2 mm in Breslow thickness to a 1 cm or ≥3 cm radial wide excision margin ( Table 49.2 ). An excision margin more conservative than that of the French group (2 cm vs 5 cm) was deemed safe by the WHO group, since the risk of local recurrence was presumed to be low in patients with melanomas ≤2 mm. Patients with melanomas on the trunk or limbs were included, excluding patients with melanomas on the face, fingers, or toes.
Of the 703 randomized patients, 612 were evaluated, and the results have been reported in three publications. The patients were stratified a priori and the results reported according to primary melanoma thickness ranges of <1 mm and 1 to 2 mm. Long-term follow-up at 4, 8 and 12 years showed no statistically significant differences in recurrence-free and overall survival rates between the 1 cm and 3 cm excision margins. In the second analysis of the trial at a mean length of follow-up of 7.5 years, four (0.6%) of the 612 patients had developed a local recurrence as a first sign of recurrent melanoma. Local recurrence was defined as a cutaneous or subcutaneous nodule occurring in the surgical scar or within a radius of 1 cm or less from the scar. All four local recurrences occurred in patients with excisions of 1 cm and with primary melanomas between 1.01 and 2.0 mm. At the time of the third analysis with a median follow-up of 12 years, 11 (1.8%) of 612 patients had developed a local recurrence as a first sign of recurrent melanoma. Eight of these recurrences occurred in patients with 1 cm excision margins, and five of these eight patients had primary melanomas between 1.01 and 2.0 mm in Breslow thickness.
This study indicated that the overall incidence of local recurrence was extremely low in patients with primary cutaneous melanomas with a Breslow thickness ≤2 mm. The risk of local recurrence appeared to be primarily a function of tumor thickness and possibly margin of excision. However, due to the low incidence of local recurrence, an impact of these factors on overall survival could not be detected, and based on the data the authors concluded that a 1 cm excision margin appeared safe in patients with melanomas ≤2 mm in thickness. Some clinicians, however, have been reluctant to adopt a 1 cm margin for all patients with melanomas ≤2 mm in thickness. Although the incidence of local recurrence is low in these patients, over time there is an absolute increase in the incidence, especially in patients with melanomas 1.01–2.0 mm in thickness. In the WHO study, the absolute number of local recurrences in the 1.01–2.0 mm cohort treated with a 1 cm margin increased from 2.5% to 3.4% in progressive follow-up reports, to an incidence of 4.2% (5 out of 119 patients) after 12 years of follow-up. The incidence of local recurrence in the same cohort of patients treated with a 3 cm excision margin was 0%, 0% and 1.5%, respectively. In patients with melanomas ≤1 mm, the incidence of local recurrence after 12 years of follow-up was 1.6% and 0.6% in patients treated with 1 and 3 cm margins of resection, respectively. Although these were not statistically different, the absolute risk of local recurrence increases over time and excision margins greater than 1 cm may be considered in patients with melanomas 1.01–2.0 mm in thickness.
The Swedish Melanoma Group Trial (melanomas >0.8–2 mm, margins 2 vs 5 cm)
The Swedish Melanoma Trial randomized patients with primary cutaneous melanomas of the trunk and extremities to a wide excision with either a 2 cm or 5 cm margin ( Tables 49.1 and 49.2 ). Between 1982 and 1991, a total of 989 patients with melanomas >0.8 mm but ≤2 mm were enrolled. The results from the study have been presented in two reports in 1996 and 2000. After a median follow-up of 8 years for local recurrence and 11 years for survival, 20% of patients experienced disease recurrence and 15% of patients had died of melanoma. There was no statistical difference in recurrence rates between the two excision cohorts.
Specifically, local recurrence, defined as recurrence in the ‘scar or transplant’, was very rare as a first event of recurrence at 0.2% (1 out of 476 patients) in patients treated with a 2 cm excision, compared to 1% (4 out of 513 patients) in the 5 cm margin cohort. This difference was not statistically different. There was a trend for increased locoregional metastasis in patients treated with a 2 cm excision. The patients in this study did not undergo sentinel lymph node biopsy, and most of the difference in locoregional metastasis was due to regional lymph node metastasis, not local or in-transit recurrences. It is possible that this trend may have been eliminated had patients with microscopic lymph node metastases been treated with early completion lymph node dissection. The estimated 10-year overall survival was not different between the two groups, 79% for patients treated with a 2 cm margin excision compared with 76% for the 5 cm group. Hence, the authors concluded that patients with melanomas >0.8 mm and ≤2.0 mm ‘can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm’. These results are similar to the ones seen in the French trial, again underscoring that in patients with primary melanomas ≤2 mm, a more conservative 2 cm margin can safely be used without apparent compromise.
The Intergroup Melanoma Surgical Trial (melanomas 1.0–4.0 mm, margins 2 vs 4 cm)
The French Melanoma Trial, the WHO Melanoma Program Trial No. 10, and the Swedish Melanoma Trial all evaluated patients with melanomas ≤2 mm and established that a 1 to 2 cm resection margin was safe in these patients. The Intergroup Melanoma Surgical Trial was initiated in 1983 and included patients with primary melanomas 1.0–4.0 mm in thickness. A total of 740 patients were enrolled into the trial and divided into two groups – Group A: proximal extremity and trunk, and Group B: head and neck, and distal extremity ( Fig. 49.1 ). The 468 patients in Group A were randomized to either a 2 cm or 4 cm margin of excision, whereas patients in Group B underwent a 2 cm excision. A second randomization of elective lymph node dissection versus nodal observation was also built into the trial for both Group A and Group B patients. All patients were a priori stratified according to tumor thickness (1.0–2.0 mm, 2.1–3.0 mm, and 3.1–4.0 mm), and presence or absence of ulceration.
The initial results from this trial were reported in 1993, and a long-term follow-up (median 10 years) was reported in 2001. Among the 468 patients in Group A (238 randomized to 2 cm vs 230 randomized to 4 cm), there was no statistical difference in local recurrence as a first event (0.4% vs 0.9%), local recurrence at any time (2.1% vs 2.6%), in-transit metastasis (5.9% vs 5.2%), and 10-year survival (70% vs 77%; P =0.074) ( Table 49.2 ). Elective lymph node dissection did not influence survival.
The median time to local recurrence was 1.7 years, and the median survival after local recurrence was only 1 year. The extent of local excision did not influence the time to local recurrence or survival after local recurrence. In a univariate analysis, local recurrence was associated with the presence of primary tumor ulceration (1.1% no ulceration vs 6.6% with ulceration; P <0.001) and increasing tumor thickness (1.0% for 1.0–2.0, 4.6% for 2.1–3.0 mm; P <0.001, 4.1% for 3.1–4.0 mm; P =0.05). In a multivariate analysis, only primary tumor ulceration was prognostic of an increased risk of local recurrence. There was a difference in local recurrence depending on the site of primary tumor location. Anytime local recurrence for tumor of the proximal extremity, trunk, distal extremity, and head or neck was 1.1%, 3.1%, 5.3%, and 9.4%, respectively.
Although there was no difference in recurrence and survival in patients undergoing a narrower 2 cm margin excision, there was a difference in the extent of surgery needed and hospital stay. Patients who underwent a 4 cm excision, compared to those who had a 2 cm excision, had a significantly longer stay in hospital (5.2 vs 3.0 days, respectively; P <0.001) and increased split-thickness skin grafting rates (46% vs 11%, respectively; P <0.001). Based on these findings, the authors concluded that 2 cm margins can safely be performed in patients with intermediate-thickness melanomas of 1.0–4.0 mm, and allows for surgery that is less disfiguring with less use of skin grafts. The longer hospital stay is less relevant today, since most patients undergoing a wide local excision for melanoma are treated on an outpatient basis.
The United Kingdom Melanoma Study Group Trial (melanomas ≥2 mm, margins 1 vs 3 cm)
In a fifth large randomized trial, the United Kingdom Melanoma Study Group, the British Association of Plastic Surgeons, and the Scottish Cancer Therapy Network randomized 900 patients with melanomas ≥2 mm to 1 cm versus 3 cm excision margins. Local recurrence was defined as recurrence within 2 cm of the scar or graft, and in-transit recurrence was defined as a recurrence from beyond the first 2 cm of the scar or graft to the regional nodes. All locoregional recurrences were detected clinically and confirmed by biopsy. Sentinel lymph node biopsy was not done as part of this trial.
After a median follow-up of 5 years, 15 (3.3%) out of 453 patients randomized to 1 cm excision experienced a local recurrence as a first event, compared to 13 (2.9%) out of 447 patients randomized to 3 cm ( Table 49.2 ). This difference was not statistically significant. However, when all locoregional recurrences (local, in-transit and regional lymph nodes) were considered, patients receiving a 1 cm margin excision had a significantly higher locoregional recurrence as first event rate of 37.1% compared to 31.8% in patients receiving 3 cm margin excisions ( P =0.05). Interestingly, the majority (85%) of locoregional first event recurrences were nodal recurrences. The overall recurrences were statistically greater in the 1 cm excision group, P =0.03. There was a trend ( P =0.06) towards decreased disease-free survival in the 1 cm excision group. There were no differences in melanoma-specific survival and overall survival between patients in the two treatment groups.
It is important to note that none of the patients in this study underwent staging of the regional lymph node basin with elective lymph node dissection or sentinel lymph node biopsy. The large proportion of regional lymph node recurrence observed in this study likely would not occur in current surgical practice since most, if not all, patients would have been offered sentinel lymph node biopsy. As a result, regional lymph node involvement would have been diagnosed earlier and would have been treated with a completion lymph node dissection, hence decreasing the risk for regional lymph node recurrence. Nonetheless, the results of this analysis do suggest that there may be a benefit in performing a wider resection to decrease the risk of locoregional recurrence.
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