Surgical Management of Melanoma Vernon K. Sondak,
MD
a,b,c,
*, Geoffrey T. Gibney,
MD
a,b
KEYWORDS Melanoma Surgery Sentinel node biopsy Lymphadenectomy Metastasectomy KEY POINTS Management of the primary melanoma: wide excision is well established for the management of primary melanoma of any stage and thickness, using guidelines based on numerous randomized clinical trials. Management of clinically negative regional nodes: sentinel node biopsy reliably identifies occult nodal metastases and provides important prognostic information that is unavailable through any other modality. Available data indicate that it should be routinely used in otherwise healthy patients with clinically node-negative melanomas greater than or equal to 0.76 mm in thickness. Management of node-positive melanoma: optimum strategies for managing nodepositive melanoma are being developed, and should be individualized based on the tumor burden within the node. Although radical lymphadenectomy should be the mainstay of treatment of any patient with macroscopic nodal disease, some patients with smallvolume microscopic disease in the sentinel node(s) do well without completion lymphadenectomy. The role of postlymphadenectomy radiation in patients with macroscopic nodal involvement, particularly when multiple nodes are involved and/or extranodal extension is present, remains controversial but randomized trial data provide strong evidence that radiation can decrease regional recurrence inside the treatment field. Management of oligometastatic melanoma: resection of limited stage IV melanoma is associated with long-term survival in a small but significant percentage of cases. As systemic therapy options improve, increasing use of preoperative therapy to improve resectability rates should be considered. Surgery also plays an important role in controlling individual lesions that have failed to respond to, or that have escaped from, treatment while other tumors in the same patient have responded or even disappeared.
Financial Disclosures: Dr V.K. Sondak is a compensated consultant for Bristol Myers Squibb, Glaxo Smith-Kline, Merck, Navidea, Novartis, and Provectus. Dr G.T. Gibney is a compensated consultant for Genentech-Roche. a Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; b Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA; c Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA * Corresponding author. 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: [email protected] Hematol Oncol Clin N Am 28 (2014) 455–470 http://dx.doi.org/10.1016/j.hoc.2014.02.009 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
456
Sondak & Gibney
INTRODUCTION
The medical management of metastatic cutaneous melanoma has changed greatly over the past several years, spurred on by progress in the understanding of the molecular biology of melanoma and of the human antitumor immune response. These scientific advances led to the development of new drugs, which proved their value in large clinical trials. In comparison, little has changed in the surgical management of localized and metastatic melanoma in the past decade, but the fundamental principles on which that surgical management is based were also established in large clinical trials and have withstood the test of time. Even with the introduction of more effective drugs for the treatment of metastatic melanoma, surgery remains the mainstay of treatment of every patient in whom complete excision of all disease is feasible, even those with regionally advanced or oligometastatic disease. In view of the rapid advances of the past few years, treatment decisions regarding the surgical and medical management of melanoma should ideally be made by a multidisciplinary team of specialists working together. For optimum results, it behooves each member of that team to understand the fundamental principles and key supporting clinical data underlying the various available management options. This article summarizes the fundamental principles and key supporting clinical data underlying the modern surgical approach to treating cutaneous melanoma of all stages. Although many of the principles described also apply to treatment of melanoma arising on mucosal surfaces, a detailed discussion of the treatment of those forms of melanoma is beyond the scope of this article. SURGICAL TREATMENT OF LOCALIZED DISEASE Surgical Treatment of Primary Melanoma
Radical wide excision (often referred to as wide local excision, a term with no intrinsic meaning because there is no such thing as a nonlocal excision) is the standard-of-care treatment of all forms of localized, biopsy-proven primary cutaneous melanoma (stages 0–III), including cases in which there is clinical evidence of regional nodal metastasis. There are 2 fundamental aspects to the radical wide excision procedure: wide excision refers to the planned removal of a predefined and measured amount of normal-appearing skin beyond the visible edge of any residual pigmentation, lesional tissue, or biopsy scar. This wide excision contrasts with the narrow excision used to biopsy suspect pigmented skin lesions, wherein the lesion is removed with only a millimeter or two (nonmeasured) of adjacent normal skin to provide the pathologist with the opportunity to examine the entirety of the clinical lesion. Radical excision indicates that the removal of normal tissue extends down to the level of the underlying muscular fascia, in contrast with the more limited amount of subcutaneous tissue that is normally excised in treatment of a typical nonmelanoma skin cancer–like basal or squamous cell carcinoma. It has never been shown that removing the muscular fascia is necessary for the success of the procedure,1,2 and practice patterns differ in whether to always, never, or selectively remove the underlying fascia.3 The width of excision for an invasive primary melanoma is based on data derived from a series of randomized controlled trials,4 and the recommended width of excision increases for thick primary tumors within the limits of anatomic constraints.5 Table 1 summarizes the recommendations for invasive cutaneous melanoma by thickness and tumor location used by most surgical oncologists, and in keeping with the current National Comprehensive Cancer Network guidelines. Although these guidelines are based on data from randomized trials, there are still unanswered
Surgical Management of Melanoma
Table 1 Recommended margins of wide excision for invasive cutaneous melanoma based on primary tumor thickness and location Recommended Excision Margin (cm)
Breslow Thickness (mm)
Primary Site
0.01–1.00
Anywhere on the skin
1
1.01–2.00
Head/neck, distal extremitya Trunk or proximal extremityb
1 2
>2.00
Head/neck, distal extremitya Trunk or proximal extremity
1 2
Note: Local anatomic constraints and specific patient factors may justify minor deviations from the standard margin recommendations. a Subungual primary tumors may require distal digital amputation. b If a skin graft would be required to reconstruct the excision defect, it is acceptable to take a 1-cm excision margin.
questions about the optimum management of primary melanoma in several clinical situations, including melanoma in situ, desmoplastic melanoma, and subungual primary tumors.6 The obvious goal of radical wide excision is to remove all visible tumor as well as microscopic extensions and any microscopic or macroscopic satellites within 1 to 2 cm of the primary site. The excision margins are measured intraoperatively on the skin; it is not expected that there will be 1 or 2 cm of histologically normal tissue beyond the last melanoma cell, only a histologically negative final margin. Histologic involvement of the resected margins sometimes necessitates further excision. Persistent positive margins after maximal excision can be a vexing problem; radiation and topical therapy with imiquimod have each been advocated but have never been proved to be effective in prospective trials. For desmoplastic melanomas, evidence is emerging that postoperative radiation can decrease local recurrence rates and should be considered in at least a subset of patients.7,8 Local recurrence after radical wide excision occurs more commonly for thick tumors; those with ulceration, angiolymphatic invasion, and/or satellitosis; and for primary tumors situated on the head and neck, palms, and soles. In a large prospective clinical trial for patients with melanoma 1 to 4 mm in thickness, patients with tumors on the trunk or proximal extremity were randomized to either a 2-cm or a 4-cm margin of excision, whereas patients with tumors on the head and neck or distal extremity were allocated to a 1-cm margin of excision.9 Overall local recurrence rates were 1.1% for the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremity, and 9.4% for the head and neck. Ulceration had a major impact on local recurrence that was statistically significant after adjusting for other prognostic factors: local recurrence was 1.1% for nonulcerated melanomas versus 6.6% for ulcerated melanomas in the randomized arms (trunk and proximal extremity) with no significant difference for those randomized to 2-cm or 4-cm margins, but was 2.1% for nonulcerated melanomas versus 16.2% for ulcerated melanomas in the nonrandomized group (distal extremity and head and neck) receiving only a 1-cm margin.9 Most guidelines call for narrower margins of excision for melanoma in situ (usually 0.5 cm) than for invasive melanoma,5 but this recommendation is not based on any prospective trial data. Lentigo maligna melanoma on the head and neck is particularly likely to be undertreated by a 0.5-cm margin,10 and is often best approached using a
457
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staged technique that allows for careful histologic evaluation of the margins before proceeding with reconstruction. For melanoma in situ arising outside the head and neck area, the difference in morbidity between a 0.5-cm margin and a 1.0-cm margin is often small enough to justify using the wider margin, especially if there is any suspicion that residual invasive melanoma might be present. Staging of the Clinically Negative Regional Lymph Nodes
After the achievement of local disease control, the next objective of surgical management of primary melanoma is frequently the staging of the regional lymph nodes. The absence or presence of microscopic tumor deposits within clinically negative lymph nodes is the most impactful predictor of long-term patient survival in clinical stage I and II melanoma,11 and, unlike the postulated situation in breast cancer, there is strong evidence that even tiny nodal micrometastases have clinical relevance.12,13 Melanoma micrometastases in the regional lymph nodes cannot reliably be detected by positron emission tomography (PET)/computed tomography (CT) scanning14,15 or even ultrasonography,16,17 but sentinel lymph node biopsy provides a low-morbidity technique for identifying these micrometastases with a high degree of accuracy.18 In 2012, an evidence-based assessment of the indications for sentinel lymph node biopsy in melanoma was issued as a joint effort of the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO).19 Their key recommendations are: Sentinel lymph node biopsy is recommended for patients with cutaneous melanomas with Breslow thickness of 1 to 4 mm at any anatomic site Sentinel lymph node biopsy may be recommended for staging purposes and to facilitate regional disease control for patients with melanomas that are greater than 4 mm in Breslow thickness There is insufficient evidence to support routine sentinel lymph node biopsy for patients with melanomas that are less than 1 mm in Breslow thickness, although it may be considered in selected high-risk patients Completion lymph node dissection is recommended for all patients with a positive sentinel lymph node biopsy (Modified from Wong and colleagues.19) The joint ASCO-SSO guideline panel found the strongest published evidence to support sentinel node biopsy for patients with intermediate-thickness melanomas, based on data provided by the interim analysis of the randomized evaluation of sentinel node biopsy, the Multicenter Selective Lymphadenectomy Trial I (MSLT-1), published in 2006.11 The final analysis of the MSLT-1 trial has been completed, and confirms and extends the findings from that interim publication (Table 2).20 These results, as well as data from large institutional series, provide support for a recommendation that sentinel lymph node biopsy be routinely used for patients with clinically node-negative thick melanomas (>4 mm) as well.21–23 The most controversial area regarding the use of sentinel node biopsy is with regard to thin melanomas (3.5 mm Nodal recurrence occurred in 5.9% of 763 patients with a negative sentinel node; 4.8% for melanomas 1.2–3.5 mm and 10.3% for melanomas >3.5 mm
Sentinel node biopsy is an effective staging procedure with an acceptable false-negative rate; true-positive and false-negative cases are more common for thick melanomas
Prognostic significance
A positive sentinel node was associated with w2.5-fold increases in disease recurrence and death from melanoma for melanomas 1.2–3.5 mm; 10-year melanoma-specific survival was 85% for patients with a negative sentinel node vs 62% for patients with a positive sentinel node
Sentinel node status is the strongest available prognostic indicator in clinically node-negative intermediate-thickness melanoma
Survival impact of sentinel node biopsy
There was a nonsignificant 3% increase in 10-year melanoma-specific survival for patients with intermediate-thickness melanoma randomized to sentinel node biopsy vs observation
Sentinel node biopsy does not significantly affect survival for all patients subjected to the procedure
Relapse-free survival impact
Patients randomized to sentinel node biopsy had a statistically significant improvement in relapse-free survival compared with observation
Sentinel node biopsy significantly reduces melanoma recurrence for intermediate and thick melanomas, mostly by markedly decreasing subsequent nodal relapse
Impact on node-positive patients
Patients with intermediate-thickness melanoma and positive nodes who were randomized to sentinel node biopsy (with completion lymphadenectomy) had a statistically significant improvement in distant metastasis-free survival and melanoma-specific survival compared with observation arm patients who had positive nodes; there was no significant difference for patients with thick melanomas and positive nodes
Early treatment of intermediate-thickness nodepositive melanoma by complete lymphadenectomy improves outcomes significantly; patients with thick node-positive melanomas may be at such high risk of distant disease that timing of lymphadenectomy loses importance
Adapted from Morton DL, Thompson JF, Cochran AJ, et al. Sentinel node biopsy or nodal observation in melanoma: final trial report. N Engl J Med 2014;370: 599–609.
Surgical Management of Melanoma
Result Feasibility
459
460
Sondak & Gibney
high-risk features for selecting patients with thin melanoma for sentinel lymph node biopsy are listed below, along with an estimate of the impact of that factor on the likelihood of finding a positive sentinel node. Thickness 0.76 to 0.99 mm
In a registry series of 1250 patients with melanomas less than or equal to 1 mm selected by a wide variety of criteria to undergo sentinel node biopsy, metastases were detected in 6.3% of 891 melanomas greater than or equal to 0.76 mm but in only 2.5% of 359 melanomas less than or equal to 0.75 mm. No metastases were detected in sentinel nodes from patients with melanomas less than 0.5 mm.27 In a large contemporary single-institution experience from a center in which sentinel node biopsy was routinely offered to patients with melanoma greater than or equal to 0.76 mm without requiring any other high-risk feature to be present, 8.4% of patients had a positive sentinel node.28 Ulceration
A positive sentinel node was present in 18.3% of patients in a registry series27 and 23.5% of patients in a single-institution series28 who had ulcerated T1 melanomas, making this rare finding (present in 8.9% and 6.6% of cases in the two series respectively) perhaps the highest risk factor for sentinel node positivity in thin melanoma. Mitotic count
The presence of even 1 dermal mitosis in a T1 melanoma upstages the tumor from T1a to T1b in the current AJCC staging system. In general, increasing mitotic counts correlate with a poorer prognosis25 and a greater likelihood of nodal metastasis for patients with cutaneous melanoma.29 The exact impact of mitotic count on the likelihood of a positive node in patients with T1 melanoma is less clear, with 1 series involving 181 cases showing that only those patients with mitotic counts greater than 0 had positive sentinel nodes, whereas other studies have found either no significant association between mitotic count and nodal status27 or have found that even cases without identified mitoses still have a 5% risk of having a positive node.28 Other factors that have been used to select patients for sentinel node biopsy include patient age, because younger patients have a higher risk of positive sentinel nodes across all tumor thickness categories29 as well as more years at risk for nodal recurrence, and Clark level greater than III.27 The latter criterion is most contentious because, within the T1 melanoma spectrum, Clark level IV melanomas are more likely to be at the thicker end (0.76 mm) where most nodal metastases are encountered. Until more evidence regarding optimum criteria for selecting patients with thin melanomas for sentinel node biopsy can be accumulated, decision making regarding this procedure should be individualized. In an editorial accompanying the ASCO-SSO sentinel node biopsy guidelines publication, Gershenwald and colleagues30 concluded that, “a rational result of this process is a recommendation for [sentinel lymph node] biopsy for many patients with melanomas 0.76–1.00 mm in thickness, but not for the overwhelming majority of patients with melanomas
MD
a,b,c,
*, Geoffrey T. Gibney,
MD
a,b
KEYWORDS Melanoma Surgery Sentinel node biopsy Lymphadenectomy Metastasectomy KEY POINTS Management of the primary melanoma: wide excision is well established for the management of primary melanoma of any stage and thickness, using guidelines based on numerous randomized clinical trials. Management of clinically negative regional nodes: sentinel node biopsy reliably identifies occult nodal metastases and provides important prognostic information that is unavailable through any other modality. Available data indicate that it should be routinely used in otherwise healthy patients with clinically node-negative melanomas greater than or equal to 0.76 mm in thickness. Management of node-positive melanoma: optimum strategies for managing nodepositive melanoma are being developed, and should be individualized based on the tumor burden within the node. Although radical lymphadenectomy should be the mainstay of treatment of any patient with macroscopic nodal disease, some patients with smallvolume microscopic disease in the sentinel node(s) do well without completion lymphadenectomy. The role of postlymphadenectomy radiation in patients with macroscopic nodal involvement, particularly when multiple nodes are involved and/or extranodal extension is present, remains controversial but randomized trial data provide strong evidence that radiation can decrease regional recurrence inside the treatment field. Management of oligometastatic melanoma: resection of limited stage IV melanoma is associated with long-term survival in a small but significant percentage of cases. As systemic therapy options improve, increasing use of preoperative therapy to improve resectability rates should be considered. Surgery also plays an important role in controlling individual lesions that have failed to respond to, or that have escaped from, treatment while other tumors in the same patient have responded or even disappeared.
Financial Disclosures: Dr V.K. Sondak is a compensated consultant for Bristol Myers Squibb, Glaxo Smith-Kline, Merck, Navidea, Novartis, and Provectus. Dr G.T. Gibney is a compensated consultant for Genentech-Roche. a Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; b Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA; c Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA * Corresponding author. 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: [email protected] Hematol Oncol Clin N Am 28 (2014) 455–470 http://dx.doi.org/10.1016/j.hoc.2014.02.009 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
456
Sondak & Gibney
INTRODUCTION
The medical management of metastatic cutaneous melanoma has changed greatly over the past several years, spurred on by progress in the understanding of the molecular biology of melanoma and of the human antitumor immune response. These scientific advances led to the development of new drugs, which proved their value in large clinical trials. In comparison, little has changed in the surgical management of localized and metastatic melanoma in the past decade, but the fundamental principles on which that surgical management is based were also established in large clinical trials and have withstood the test of time. Even with the introduction of more effective drugs for the treatment of metastatic melanoma, surgery remains the mainstay of treatment of every patient in whom complete excision of all disease is feasible, even those with regionally advanced or oligometastatic disease. In view of the rapid advances of the past few years, treatment decisions regarding the surgical and medical management of melanoma should ideally be made by a multidisciplinary team of specialists working together. For optimum results, it behooves each member of that team to understand the fundamental principles and key supporting clinical data underlying the various available management options. This article summarizes the fundamental principles and key supporting clinical data underlying the modern surgical approach to treating cutaneous melanoma of all stages. Although many of the principles described also apply to treatment of melanoma arising on mucosal surfaces, a detailed discussion of the treatment of those forms of melanoma is beyond the scope of this article. SURGICAL TREATMENT OF LOCALIZED DISEASE Surgical Treatment of Primary Melanoma
Radical wide excision (often referred to as wide local excision, a term with no intrinsic meaning because there is no such thing as a nonlocal excision) is the standard-of-care treatment of all forms of localized, biopsy-proven primary cutaneous melanoma (stages 0–III), including cases in which there is clinical evidence of regional nodal metastasis. There are 2 fundamental aspects to the radical wide excision procedure: wide excision refers to the planned removal of a predefined and measured amount of normal-appearing skin beyond the visible edge of any residual pigmentation, lesional tissue, or biopsy scar. This wide excision contrasts with the narrow excision used to biopsy suspect pigmented skin lesions, wherein the lesion is removed with only a millimeter or two (nonmeasured) of adjacent normal skin to provide the pathologist with the opportunity to examine the entirety of the clinical lesion. Radical excision indicates that the removal of normal tissue extends down to the level of the underlying muscular fascia, in contrast with the more limited amount of subcutaneous tissue that is normally excised in treatment of a typical nonmelanoma skin cancer–like basal or squamous cell carcinoma. It has never been shown that removing the muscular fascia is necessary for the success of the procedure,1,2 and practice patterns differ in whether to always, never, or selectively remove the underlying fascia.3 The width of excision for an invasive primary melanoma is based on data derived from a series of randomized controlled trials,4 and the recommended width of excision increases for thick primary tumors within the limits of anatomic constraints.5 Table 1 summarizes the recommendations for invasive cutaneous melanoma by thickness and tumor location used by most surgical oncologists, and in keeping with the current National Comprehensive Cancer Network guidelines. Although these guidelines are based on data from randomized trials, there are still unanswered
Surgical Management of Melanoma
Table 1 Recommended margins of wide excision for invasive cutaneous melanoma based on primary tumor thickness and location Recommended Excision Margin (cm)
Breslow Thickness (mm)
Primary Site
0.01–1.00
Anywhere on the skin
1
1.01–2.00
Head/neck, distal extremitya Trunk or proximal extremityb
1 2
>2.00
Head/neck, distal extremitya Trunk or proximal extremity
1 2
Note: Local anatomic constraints and specific patient factors may justify minor deviations from the standard margin recommendations. a Subungual primary tumors may require distal digital amputation. b If a skin graft would be required to reconstruct the excision defect, it is acceptable to take a 1-cm excision margin.
questions about the optimum management of primary melanoma in several clinical situations, including melanoma in situ, desmoplastic melanoma, and subungual primary tumors.6 The obvious goal of radical wide excision is to remove all visible tumor as well as microscopic extensions and any microscopic or macroscopic satellites within 1 to 2 cm of the primary site. The excision margins are measured intraoperatively on the skin; it is not expected that there will be 1 or 2 cm of histologically normal tissue beyond the last melanoma cell, only a histologically negative final margin. Histologic involvement of the resected margins sometimes necessitates further excision. Persistent positive margins after maximal excision can be a vexing problem; radiation and topical therapy with imiquimod have each been advocated but have never been proved to be effective in prospective trials. For desmoplastic melanomas, evidence is emerging that postoperative radiation can decrease local recurrence rates and should be considered in at least a subset of patients.7,8 Local recurrence after radical wide excision occurs more commonly for thick tumors; those with ulceration, angiolymphatic invasion, and/or satellitosis; and for primary tumors situated on the head and neck, palms, and soles. In a large prospective clinical trial for patients with melanoma 1 to 4 mm in thickness, patients with tumors on the trunk or proximal extremity were randomized to either a 2-cm or a 4-cm margin of excision, whereas patients with tumors on the head and neck or distal extremity were allocated to a 1-cm margin of excision.9 Overall local recurrence rates were 1.1% for the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremity, and 9.4% for the head and neck. Ulceration had a major impact on local recurrence that was statistically significant after adjusting for other prognostic factors: local recurrence was 1.1% for nonulcerated melanomas versus 6.6% for ulcerated melanomas in the randomized arms (trunk and proximal extremity) with no significant difference for those randomized to 2-cm or 4-cm margins, but was 2.1% for nonulcerated melanomas versus 16.2% for ulcerated melanomas in the nonrandomized group (distal extremity and head and neck) receiving only a 1-cm margin.9 Most guidelines call for narrower margins of excision for melanoma in situ (usually 0.5 cm) than for invasive melanoma,5 but this recommendation is not based on any prospective trial data. Lentigo maligna melanoma on the head and neck is particularly likely to be undertreated by a 0.5-cm margin,10 and is often best approached using a
457
458
Sondak & Gibney
staged technique that allows for careful histologic evaluation of the margins before proceeding with reconstruction. For melanoma in situ arising outside the head and neck area, the difference in morbidity between a 0.5-cm margin and a 1.0-cm margin is often small enough to justify using the wider margin, especially if there is any suspicion that residual invasive melanoma might be present. Staging of the Clinically Negative Regional Lymph Nodes
After the achievement of local disease control, the next objective of surgical management of primary melanoma is frequently the staging of the regional lymph nodes. The absence or presence of microscopic tumor deposits within clinically negative lymph nodes is the most impactful predictor of long-term patient survival in clinical stage I and II melanoma,11 and, unlike the postulated situation in breast cancer, there is strong evidence that even tiny nodal micrometastases have clinical relevance.12,13 Melanoma micrometastases in the regional lymph nodes cannot reliably be detected by positron emission tomography (PET)/computed tomography (CT) scanning14,15 or even ultrasonography,16,17 but sentinel lymph node biopsy provides a low-morbidity technique for identifying these micrometastases with a high degree of accuracy.18 In 2012, an evidence-based assessment of the indications for sentinel lymph node biopsy in melanoma was issued as a joint effort of the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO).19 Their key recommendations are: Sentinel lymph node biopsy is recommended for patients with cutaneous melanomas with Breslow thickness of 1 to 4 mm at any anatomic site Sentinel lymph node biopsy may be recommended for staging purposes and to facilitate regional disease control for patients with melanomas that are greater than 4 mm in Breslow thickness There is insufficient evidence to support routine sentinel lymph node biopsy for patients with melanomas that are less than 1 mm in Breslow thickness, although it may be considered in selected high-risk patients Completion lymph node dissection is recommended for all patients with a positive sentinel lymph node biopsy (Modified from Wong and colleagues.19) The joint ASCO-SSO guideline panel found the strongest published evidence to support sentinel node biopsy for patients with intermediate-thickness melanomas, based on data provided by the interim analysis of the randomized evaluation of sentinel node biopsy, the Multicenter Selective Lymphadenectomy Trial I (MSLT-1), published in 2006.11 The final analysis of the MSLT-1 trial has been completed, and confirms and extends the findings from that interim publication (Table 2).20 These results, as well as data from large institutional series, provide support for a recommendation that sentinel lymph node biopsy be routinely used for patients with clinically node-negative thick melanomas (>4 mm) as well.21–23 The most controversial area regarding the use of sentinel node biopsy is with regard to thin melanomas (3.5 mm Nodal recurrence occurred in 5.9% of 763 patients with a negative sentinel node; 4.8% for melanomas 1.2–3.5 mm and 10.3% for melanomas >3.5 mm
Sentinel node biopsy is an effective staging procedure with an acceptable false-negative rate; true-positive and false-negative cases are more common for thick melanomas
Prognostic significance
A positive sentinel node was associated with w2.5-fold increases in disease recurrence and death from melanoma for melanomas 1.2–3.5 mm; 10-year melanoma-specific survival was 85% for patients with a negative sentinel node vs 62% for patients with a positive sentinel node
Sentinel node status is the strongest available prognostic indicator in clinically node-negative intermediate-thickness melanoma
Survival impact of sentinel node biopsy
There was a nonsignificant 3% increase in 10-year melanoma-specific survival for patients with intermediate-thickness melanoma randomized to sentinel node biopsy vs observation
Sentinel node biopsy does not significantly affect survival for all patients subjected to the procedure
Relapse-free survival impact
Patients randomized to sentinel node biopsy had a statistically significant improvement in relapse-free survival compared with observation
Sentinel node biopsy significantly reduces melanoma recurrence for intermediate and thick melanomas, mostly by markedly decreasing subsequent nodal relapse
Impact on node-positive patients
Patients with intermediate-thickness melanoma and positive nodes who were randomized to sentinel node biopsy (with completion lymphadenectomy) had a statistically significant improvement in distant metastasis-free survival and melanoma-specific survival compared with observation arm patients who had positive nodes; there was no significant difference for patients with thick melanomas and positive nodes
Early treatment of intermediate-thickness nodepositive melanoma by complete lymphadenectomy improves outcomes significantly; patients with thick node-positive melanomas may be at such high risk of distant disease that timing of lymphadenectomy loses importance
Adapted from Morton DL, Thompson JF, Cochran AJ, et al. Sentinel node biopsy or nodal observation in melanoma: final trial report. N Engl J Med 2014;370: 599–609.
Surgical Management of Melanoma
Result Feasibility
459
460
Sondak & Gibney
high-risk features for selecting patients with thin melanoma for sentinel lymph node biopsy are listed below, along with an estimate of the impact of that factor on the likelihood of finding a positive sentinel node. Thickness 0.76 to 0.99 mm
In a registry series of 1250 patients with melanomas less than or equal to 1 mm selected by a wide variety of criteria to undergo sentinel node biopsy, metastases were detected in 6.3% of 891 melanomas greater than or equal to 0.76 mm but in only 2.5% of 359 melanomas less than or equal to 0.75 mm. No metastases were detected in sentinel nodes from patients with melanomas less than 0.5 mm.27 In a large contemporary single-institution experience from a center in which sentinel node biopsy was routinely offered to patients with melanoma greater than or equal to 0.76 mm without requiring any other high-risk feature to be present, 8.4% of patients had a positive sentinel node.28 Ulceration
A positive sentinel node was present in 18.3% of patients in a registry series27 and 23.5% of patients in a single-institution series28 who had ulcerated T1 melanomas, making this rare finding (present in 8.9% and 6.6% of cases in the two series respectively) perhaps the highest risk factor for sentinel node positivity in thin melanoma. Mitotic count
The presence of even 1 dermal mitosis in a T1 melanoma upstages the tumor from T1a to T1b in the current AJCC staging system. In general, increasing mitotic counts correlate with a poorer prognosis25 and a greater likelihood of nodal metastasis for patients with cutaneous melanoma.29 The exact impact of mitotic count on the likelihood of a positive node in patients with T1 melanoma is less clear, with 1 series involving 181 cases showing that only those patients with mitotic counts greater than 0 had positive sentinel nodes, whereas other studies have found either no significant association between mitotic count and nodal status27 or have found that even cases without identified mitoses still have a 5% risk of having a positive node.28 Other factors that have been used to select patients for sentinel node biopsy include patient age, because younger patients have a higher risk of positive sentinel nodes across all tumor thickness categories29 as well as more years at risk for nodal recurrence, and Clark level greater than III.27 The latter criterion is most contentious because, within the T1 melanoma spectrum, Clark level IV melanomas are more likely to be at the thicker end (0.76 mm) where most nodal metastases are encountered. Until more evidence regarding optimum criteria for selecting patients with thin melanomas for sentinel node biopsy can be accumulated, decision making regarding this procedure should be individualized. In an editorial accompanying the ASCO-SSO sentinel node biopsy guidelines publication, Gershenwald and colleagues30 concluded that, “a rational result of this process is a recommendation for [sentinel lymph node] biopsy for many patients with melanomas 0.76–1.00 mm in thickness, but not for the overwhelming majority of patients with melanomas
