“Of blacke cholor [bile], without boyling cometh cancer.”
– Thomas Gale
Background
Melanoma, what Sidney Farber once called “the black cancer,” spreads insidiously throughout the body causing recurrence and metastasis if not completely excised. Recommendations for melanoma excision margins have evolved with our understanding of tumor growth and recurrence risk. Wide local excision (WLE), the current standard of care, involves resecting clinically apparent cancerous tissue along with an additional margin of healthy tissue, typically in a fusiform excision. Ninety percent of all patients with melanoma in situ (MIS) receive this treatment, and recurrence rates have generally been found to be <10%.1,2 In recent years, Mohs micrographic surgery (MMS) has emerged as a promising potential treatment modality for MIS, boasting retrospective recurrence rates as low as 0.3%, coupled with the added benefit of skin preservation.3 Originally developed for nonmelanoma skin cancers, MMS involves multiple stages of excision and histopathologic tissue assessment until the margins are clear of malignant cells. Stepwise excisions with complete histologic assessment of margins allow for maximum preservation of healthy tissue while ensuring complete tumor removal. Although the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous Melanoma reference studies on the use of MMS in the surgical management of MIS, MMS is not currently recommended in most cases.4 This likely reflects the absence of consensus and high-quality prospective data on this topic.
Despite the potential advantages of MMS for MIS treatment, heterogeneity in its practice complicates the generalizability of existing data and impedes its future study in clinical trials. The quality of margin assessment during MMS may depend on variables such as the choice of starting peripheral margin, method of tissue debulk processing, use of immunohistochemical stains, and use of negative tissue control.5 The lack of a consensus approach hampers comparisons across studies and makes it difficult to draw definitive conclusions on the optimal application of MMS for MIS treatment. Furthermore, prospective trials evaluating the use of MMS for MIS are still lacking. Consequently, a considerable portion of the existing literature, including the articles referenced in this study, are significantly constrained by their retrospective nature, methodological heterogeneity, short follow-up periods, and reliance on self-reported outcomes.
This study contributes to the development of standardized protocols and guidelines for MMS for future clinical trials in melanoma by convening MMS experts to achieve consensus on the optimal techniques. The Delphi methodology was selected due to the wide range of surgical techniques used for treating MIS with MMS, the limited existing data on optimal surgical practices, and the intention to establish an expert-guided standardized protocol. The methodology adheres to the CREDES recommendations set forth by Jünger et al6 to ensure quality and transparency.
Methods
Study Design
The Delphi technique is a widely accepted methodology for facilitating consensus among a group of experts on questions for which either limited objective evidence, or the infeasibility of collecting such evidence, means professional judgment is required to arrive at an answer. The technique involves surveying an expert panel over multiple rounds, analyzing the results of each round, and presenting the results to the panelists as “controlled feedback” that they may use to alter or inform their answers in the next round.7 Survey questions in subsequent rounds also may be modified in response to expert feedback. After a set number of rounds, the study concludes with each surveyed item either reaching or failing to reach a predefined threshold for consensus. The Delphi process used in this study comprised 2 rounds.
Item Generation
A literature review was conducted in August 2022 to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. Simultaneously, expert Mohs micrographic surgeons were consulted and interviewed to gather their perspectives on the techniques that would benefit from standardization. Using affinity mapping, data from the literature review and the interviews were combined, resulting in 8 dimensions of MMS for MIS that showed significant technical variation among surgeons and lacked guidelines or prospective literature (Table 1).
The 8 Consensus Recommendations for Mohs Surgeons Treating Melanoma in Situ
Summary of Existing Literature
Two members of the research team independently generated summaries of the existing literature for each of the 8 selected dimensions using multiple databases, including ScienceDirect and PubMed. A reference librarian was available if needed. The summaries were later reconciled to ensure an accurate representation of the available literature. These summaries were intended to guide panelists who wished to quickly familiarize themselves with the available literature for a specific surgical dimension.
The summaries assessed the technical variations for each dimension using 3 main criteria: (1) impact on cure rate, (2) impact on tissue conservation, and (3) impact on cost, including both time and money. References were provided for each of these 3 criteria for every surgical dimension, which are shown in Supplementary Table S1 in the (available online with this article). In addition, the overall quality of the evidence for each dimension was assessed using a modified version of the Center for Evidence-Based Medicine levels of evidence grading criteria.8 It was clearly stated when a criterion for a surgical dimension had limited or no evidence available.
Finally, participants were encouraged to review the summaries and suggest any additional references they deemed relevant. They were also invited to contest any references included in the summaries. Participants were assured that any changes to the summaries, including all comments, additional references, or suggested removals by a participant, would be shared with the entire panel in a deidentified format to maintain transparency and integrity of the Delphi process.
Participant Selection
Expert Mohs micrographic surgeons were selected as participants using the following criteria: fellowship-trained in Mohs micrographic surgery, currently practicing MMS with membership in the American College of Mohs Surgery, possessing >5 years of experience, and managing at least 50 melanoma cases annually. A total of 44 Mohs surgeons representing academic institutions from across the United States were included as participants in this study.
Data Collection
Study data were collected and managed using REDCap electronic data capture tools hosted at University Hospitals Cleveland Medical Center and Oregon Health & Science University.9,10 REDCap is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources.
First Round of the Delphi
In Round 1, participants were sent a REDCap form containing an introduction to the Delphi process followed by the consensus questions. For each of the 8 surgical dimensions investigated, participants received the aforementioned one-page summary of the existing literature. A preliminary proposed recommendation on the optional method was presented in light of the available evidence (Table 1). Participants were asked to rate their level of agreement with the recommendation using a 9-point Likert scale. Ratings of 7 through 9 were defined as “agreement,” 4 through 6 as “neutral,” and 1 through 3 as “disagreement.” Consensus was defined a priori as agreement of at least 70% of participants. Participants who disagreed were presented with a free text box and asked to elaborate on any reasoning, evidence, or literature sources that led them to disagree.
Second Round of the Delphi
In Round 2, participants were given a statistical summary of the panel’s Likert scale responses for each recommendation. This summary included a histogram, median and mean rating values, and a stacked bar chart showing the percentage of participants falling into the “agree,” “neutral,” and “disagree.” For recommendations that reached the prespecified threshold for consensus in Round 1, the participants were asked if they had any further comments. For those that did not reach consensus, 2 experts in MMS analyzed and synthesized comments left by participants to elicit the key disagreements with the proposed recommendation. In response to these disagreements, a second literature search was conducted to refine the supporting and contradicting evidence. The results of this search informed a written discussion for each reason for disagreement and a final conclusion to either retain the original recommendation or modify it. Each area of disagreement, its discussion with references, and the modified recommendations were presented to the participants in Round 2. Participants were subsequently asked to either agree or disagree with each refined recommendation and to support their answer if they disagreed.
Findings
The expert panel reached consensus on 5 of the 8 dimensions after Round 1 and on the remaining 3 dimensions after Round 2. The consensus statements along with the levels of agreement are provided in Table 1.
1. Wood’s Lamp
Some surgeons use a Wood’s lamp to identify lesion borders for an initial surgical margin, but no literature was found to support this practice. One study demonstrated that margins determined by Wood’s lamp were larger than clinically determined margins, implying potential removal of benign tissue.11 Another study corroborated this concern, demonstrating that Wood’s lamp would have increased the wound size in all cases, with the excess tissue removed containing no melanoma in 86% of cases.12 Neither does the evidence support that Wood’s lamp improves accuracy: one study showed that 92% of patients required additional stages beyond the margins identified by Wood’s lamp, with all resulting wound sizes larger than these margins.10 Because the microscopic examination performed in MMS is the gold standard for identifying melanoma cells, the lower accuracy of Wood’s lamp offers little benefit to offset its potential risk of removing excess tissue. Although some panelists suggested limited use of Wood’s lamp in Round 1, after deliberation of the evidence described earlier, the panel reached consensus in Round 2 to recommend against the use of Wood’s lamp.
2. Dermatoscope
Limited evidence exists regarding the impact of dermoscopy on cure rate, tissue conservation, or cost. One case series demonstrated that margins determined by dermatoscope were larger than those determined both clinically and by Wood’s lamp.11 In other skin cancers, use of dermoscopy resulted in larger initial margins but no reduction in the number of surgical rounds.13 The panel agreed that use of dermoscopy should be left up to each individual surgeon.
3. Negative Tissue Control
Multiple studies have shown wide person-to-person variation in melanocyte density and frequent cytologic atypia in non–sun-damaged skin.14 Consequently, many Mohs surgeons sample control tissue with equivalent photodamage to the lesion site to distinguish true tumor margin from background melanocytic atypia. By helping to precisely identify tumor borders, negative tissue controls have been shown to decrease false-positive margin interpretation,15 which preserves healthy tissue.16 The panel reached consensus in Round 2 to recommend use of a negative tissue control from a site of equivalent light exposure at least 10 cm away from the surgical site.
4. Debulk Specimens
Between 5% and 20% of melanomas are upstaged upon histopathologic examination of a debulk specimen.17 Upstaging of the primary tumor may prompt sentinel lymph node biopsy to detect regional or metastatic spread. Thus, histopathologic examination of the debulk specimen is considered standard of care.
The method of debulk specimen examination varies, with some surgeons examining the debulk using frozen sections and others fixing the debulk for permanent section examination.18 Although paraffin sections are still considered the gold standard for diagnostic accuracy, multiple studies have shown the equivalent accuracy of frozen sections with immunostaining.3,15,19 Frozen sectioning has the added benefit of allowing instant upstaging so that lymph node biopsy can be performed before reconstruction, which is cost-effective and may preserve lymphatic drainage for accurate sentinel lymph node biopsy.20 The panel reached consensus that a debulk specimen should be removed and vertically sectioned. The panel also recommended leaving the particular method of processing, whether frozen or permanent, up to the discretion of each surgeon.
5. Starting Peripheral Margin
Current literature contains varying discussions and reports regarding the ideal margin size for excising MIS with MMS to minimize the chances of recurrence and encourage tissue preservation. There exists an even greater paucity of data and a notable variation in the recommended initial margin size. One study found that approximately 55% of lesions were cleared with 3-mm margins, advancing to 100% clearance at 12 mm.21 Other studies suggest clear margins can be obtained in most cases with total margins ≤6 mm.22 The panel reached consensus that the starting peripheral margin should be ≤5 mm.
6. Excision Depth
The optimal depth of excision has historically been a topic severely lacking in empirical evidence. As yet, no randomized controlled trials exist to inform current guidelines. For MIS, current NCCN Guidelines state “depth of excision into the subcutaneous fat may be adequate and considered in anatomic locations where excision to fascia would cause significant morbidity.”4 The panel reached consensus that MIS should be resected to the subcutaneous fat, but not necessarily to the fascia.
7. Tissue Processing
Some Mohs surgeons send a final peripheral margin for permanent sectioning confirmation after they have cleared a melanoma by Mohs surgery, whereas others rely on frozen section interpretation. The evaluation of melanocytic lesions on frozen sections is challenging. Melanocytes can retain their pericytoplasmic vacuolization better with permanent sections, making them easier to identify. Frozen sections may be more susceptible to artifacts such as folding, freeze artifact, and keratinocyte vacuolization, which can lead to the incorrect interpretation of melanocytic lesions. Additionally, it has been noted that determining whether single atypical melanocytes are indicative of chronic sun damage or the periphery of MIS poses a challenge.14
However, several studies support the accuracy of frozen sections, particularly with modern immunostaining. One study demonstrated that surgeons detected melanoma on frozen sections with MART-1 with a sensitivity of 95.3% and a specificity of 95.1% compared with the dermatopathologist’s permanent section interpretation of the same study specimen.23 A recent retrospective analysis found an overall concordance rate of 96.8% between MART-1 frozen and permanent sections.24
The panel reached consensus that frozen sections should be used instead of permanent sections for final margin confirmation. This recommendation refers to final margin confirmation after excision of MIS by Mohs surgery with frozen sections. Other methods, such as staged excision with permanent sectioning, are distinct and this recommendation does not apply to those methods.
8. Immunohistochemistry
The use of immunostain was the least controversial technique in the literature but was included in this consensus study due to the lack of prospective data regarding its use in MMS for MIS. Multiple reports describe the efficacy of using an immunostain in combination with frozen sections to achieve rapid and accurate assessment of margins.3,15,19 MART-1 is the most commonly used immunostain, but there have been no randomized trials demonstrating the superiority of one immunostain over another.5 The panel agreed that at least one immunostain should be used, with the particular immunostain left to the discretion of each surgeon.
Discussion
In this study, 44 experts of MMS for MIS collaborated via a Delphi process to establish consensus recommendations for 8 key dimensions of technical variation that currently lack data-driven guidelines. Techniques achieving consensus in Round 1 included use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus was established in Round 2 on the use of Wood’s lamp, dermatoscope, and negative tissue controls.
Use of MMS for treatment of MIS remains somewhat controversial. Although WLE remains the standard-of-care surgical treatment for invasive melanomas, use of MMS for MIS has increased over the past 20 years.25 Both approaches offer advantages and disadvantages for treatment of MIS.26 Disadvantages of WLE include a 4% chance of positive margin requiring re-excision, and, because vertical sectioning techniques examine a fraction of the surgical margin, an increased concern for recurrence.27 In contrast, MMS examines the entire margin and allows for tissue preservation, but differentiation between background melanocytic hyperplasia and true MIS may be difficult with frozen sectioning.26 A recent Delphi study reported consensus with 83% agreement that staged surgical excision with margin control is the most appropriate treatment for the lentigo melanoma variant of MIS. However, only 43% in that study agreed that MMS in particular was most appropriate.28 Although retrospective studies have shown comparable or even improved recurrence rates with MMS compared with WLE, no prospective trial comparing these 2 methods has yet been performed.3
This study addresses several existing controversies in the use of MMS for MIS. In particular, the results of this study provide an expert consensus on the most common technical variations when performing MMS for MIS. This consensus is important because technical variation is a major source of heterogeneity in existing data.5 One limitation of this study was the potential for bias in the summaries and references provided to panelists both before the first round of the survey and in between the first and second round. Although every effort was made to ensure that any summarized evidence was presented comprehensively and in neutral language, and although the panelists were invited to offer additional references, comments, disagreements, or suggestions to the summaries provided, inadvertent biases on the part of the authors may have occurred nevertheless.
Conclusions
This study may act as a foundation for future clinical trials that seek to prospectively validate use of MMS for melanoma by establishing an expert consensus on best practices for the Mohs treatment arm. Although this study addressed 8 important aspects of the MMS technique that lacked standardization, future studies are needed to explore others that were not evaluated. These may include standardizing laboratory practices, tissue section thickness, defining appropriate trimming of the tissue block, and approach to atypical melanocytic hyperplasia.
References
- 1.↑
Friedman EB, Scolyer RA, Williams GJ, et al. Melanoma in situ: a critical review and re-evaluation of current excision margin recommendations. Adv Ther 2021;38:3506–3530.
- 2.↑
Sharma AN, Foulad DP, Doan L, et al. Mohs surgery for the treatment of lentigo maligna and lentigo maligna melanoma – a systematic review. J Dermatolog Treat 2021;32:157–163.
- 3.↑
Etzkorn JR, Sobanko JF, Elenitsas R, et al. Low recurrence rates for in situ and invasive melanomas using Mohs micrographic surgery with melanoma antigen recognized by T cells 1 (MART-1) immunostaining: tissue processing methodology to optimize pathologic staging and margin assessment. J Am Acad Dermatol 2015;72:840–850.
- 4.↑
Swetter SM, Johnson D, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous. Version 1.2024. Accessed March 15, 2024. To view the most recent version, visit https://www.nccn.org
- 5.↑
Krausz AE, Higgins HW II, Etzkorn J, et al. Systematic review of technical variations for Mohs micrographic surgery for melanoma. Dermatol Surg 2021;47:1539–1544.
- 6.↑
Jünger S, Payne SA, Brine J, et al. Guidance on conducting and reporting Delphi studies (CREDES) in palliative care: recommendations based on a methodological systematic review. Palliat Med 2017;31:684–706.
- 7.↑
Rowe G, Wright G. The Delphi technique as a forecasting tool: issues and analysis. Int J Forecast 1999;15:353–375.
- 8.↑
Oxford University. Oxford Centre for Evidence-Based Medicine: levels of evidence (March 2009). Accessed February 4, 2024. Available at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009
- 9.↑
Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–381.
- 10.↑
Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform 2019;95:103208.
- 11.↑
Robinson JK. Use of digital epiluminescence microscopy to help define the edge of lentigo maligna. Arch Dermatol 2004;140:1095–1100.
- 12.↑
Walsh SB, Varma R, Raimer D, et al. Utility of Wood’s light in margin determination of melanoma in situ after excisional biopsy. Dermatol Surg 2015;41:572–578.
- 13.↑
Suzuki HS, Serafini SZ, Sato MS. Utility of dermoscopy for demarcation of surgical margins in Mohs micrographic surgery. An Bras Dermatol 2014;89:38–43.
- 14.↑
Beaulieu D, Fathi R, Srivastava D, et al. Current perspectives on Mohs micrographic surgery for melanoma. Clin Cosmet Investig Dermatol 2018;11:309–320.
- 15.↑
Chang KH, Finn DT, Lee D, et al. Novel 16-minute technique for evaluating melanoma resection margins during Mohs surgery. J Am Acad Dermatol 2011;64:107–112.
- 16.↑
Albertini JG, Elston DM, Libow LF, et al. Mohs micrographic surgery for melanoma: a case series, a comparative study of immunostains, an informative case report, and a unique mapping technique. Dermatol Surg 2002;28:656–665.
- 17.↑
Iorizzo LJ III, Chocron I, Lumbang W, et al. Importance of vertical pathology of debulking specimens during Mohs micrographic surgery for lentigo maligna and melanoma in situ. Dermatol Surg 2013;39:365–371.
- 18.↑
Siscos SM, Neill BC, Seger EW, et al. The current state of Mohs surgery for the treatment of melanoma: a nationwide cross-sectional survey of Mohs surgeons. Dermatol Surg 2020;46:1267–1271.
- 19.↑
Cherpelis BS, Moore R, Ladd S, et al. Comparison of MART-1 frozen sections to permanent sections using a rapid 19-minute protocol. Dermatol Surg 2009;35:207–213.
- 20.↑
Morton DL. Sentinel lymphadenectomy for patients with clinical stage I melanoma. J Surg Oncol 1997;66:267–269.
- 21.↑
Foxton GC, Elliott TG, Litterick KA. Treating melanoma in situ and lentigo maligna with Mohs micrographic surgery in Australia. Australas J Dermatol 2019;60:33–37.
- 22.↑
Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol 2012;66:438–444.
- 23.↑
Bhatt MD, Perz AM, Moioli E, et al. The accuracy of detecting melanoma on frozen section melanoma antigen recognized by T cells 1 (MART-1) stains and on permanent sections of previously frozen tissue: a prospective cohort study. J Am Acad Dermatol 2021;84:1764–1766.
- 24.↑
Young JN, Nguyen TA, Freeman SC, et al. Permanent section margin concordance after Mohs micrographic surgery with immunohistochemistry for invasive melanoma and melanoma in situ: a retrospective dual-center analysis. J Am Acad Dermatol 2023;88:1060–1065.
- 25.↑
Lee MP, Sobanko JF, Shin TM, et al. Evolution of excisional surgery practices for melanoma in the United States. JAMA Dermatol 2019;155:1244–1251.
- 26.↑
Abrantes T, Robbins A, Kahn B, et al. Understanding melanoma in situ: lentigo maligna surgical treatment terminology and guideline adherence, a targeted review. J Am Acad Dermatol 2023;89:734–744.
- 27.↑
Miller CJ, Shin TM, Sobanko JF, et al. Risk factors for positive or equivocal margins after wide local excision of 1345 cutaneous melanomas. J Am Acad Dermatol 2017;77:333–340.e1.
- 28.↑
Longo C, Navarrete-Dechent C, Tschandl P, et al. Delphi consensus among international experts on the diagnosis, management, and surveillance for lentigo maligna. Dermatol Pract Concept 2023;13:e2023244.
