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E-IJD® - CURRENT PERSPECTIVE
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 479
Mohs micrographic surgery for melanoma: A convincing treatment modality


1 From the Department of Dermatology, University of Maryland Medical Center, Baltimore, MD, USA
2 Department of Dermatology, Veterans Affairs Medical Center; Department of Dermatology, SUNY Downstate, Brooklyn, NY, USA

Date of Web Publication2-Nov-2022

Correspondence Address:
Amor Khachemoune
Veterans Affairs Hospital and SUNY Downstate Dermatology Service, 800 Poly Place, Brooklyn, NY 11209
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_1074_20

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   Abstract 


Mohs micrographic surgery (MMS) is the gold standard for treating keratinocyte carcinomas in specific locations or due to other tumor-specific factors, given its comprehensive margin assessment, tissue sparing, and high cure rate. The use of MMS for treating invasive melanoma with intraoperative immunostains is still a subject of debate. Herein, a literature review supports the following recommendations. In cosmetically or functionally demanding sites such as head, neck, hands, feet, and pretibial leg, we recommend MMS for MMIS and all thin melanomas measuring <0.8 mm Breslow depth. Additionally, on the head and neck, all superficial spreading and lentigo maligna melanoma (LMM) histologic subtypes <0.8 mm Breslow depth should be treated with MMS. We recommend using melanoma antigen recognized by T cells 1 (MART-1) immunostain intraoperatively given its high sensitivity. However, microphthalmia transcription factor (MITF) and Sry-related HMG-Box gene 10 (SOX10) are useful adjuncts for difficult cases.


Keywords: Melanocyte, melanoma, Mohs micrographic surgery, tumor progression


How to cite this article:
Clements S, Khachemoune A. Mohs micrographic surgery for melanoma: A convincing treatment modality. Indian J Dermatol 2022;67:479

How to cite this URL:
Clements S, Khachemoune A. Mohs micrographic surgery for melanoma: A convincing treatment modality. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 4];67:479. Available from: https://www.e-ijd.org/text.asp?2022/67/4/479/360296





   Introduction Top


Mohs micrographic surgery (MMS) is the gold standard for treating keratinocyte carcinomas in areas with increased cosmetic and functional importance, such as the head and neck, given its comprehensive margin assessment, tissue sparing, and high cure rate. Mohs micrographic surgery is commonly employed for melanoma in situ (MMIS), yet it is not routinely used for invasive melanoma. The most significant hindrance to its use is the perceived difficulty of interpreting atypical melanocytic proliferations on frozen section slides. However, this has been ameliorated in recent years by using immunostains.[1] Furthermore, differences in fellowship training among Mohs surgeons, individual surgeon preferences, and debates in the literature may also contribute to the lack of agreement on the proper use of MMS for the treatment of melanoma.[2]

The incidence of cutaneous melanoma in the United States is rising, with 96,480 new cases diagnosed in 2019.[3] The current National Comprehensive Cancer Network (NCCN) guidelines recommend wide local excision (WLE) for invasive melanoma and that MMS be considered for complete margin assessment in lentigo maligna (LM) and MMIS, given their potential for subclinical extension.[4] For invasive melanoma, the same surgical margin is recommended regardless of anatomic location, without mentioning MMS as a treatment option.[4] In contrast, Rzepecki et al.[5] posit that melanomas in anatomic areas of increased cosmetic and functional significance, such as the head and neck, hands and feet, genitalia, and pretibial leg, MMS should be favored. This group found that patients treated with WLE had higher rates of upstaging, positive margins, local recurrence, and the need for complex reconstruction compared to those treated with MMS.[5] Other studies collaborate with these findings, demonstrating lower recurrence rates and improved or non-inferior survival outcomes of MMS for the treatment of MMIS or invasive melanoma compared to WLE.[1],[6],[7] Thus, there is a growing body of evidence suggesting that MMS is a better option than WLE for treating invasive melanoma on these sites.

In this article, we seek to critically review the available data regarding MMS for treating MMIS and invasive melanoma and reappraise the appropriateness of its use for these entities.


   Discussion Top


NCCN guidelines for melanoma treatment

The NCCN guidelines base their recommendations for WLE of all primary melanomas, regardless of anatomic location, on data from six prospective trials.[5],[8],[9],[10],[11],[12],[13] These trials randomized invasive melanoma patients with Breslow depth greater than 2 millimeters (mm) to conventional excision with postoperative margin assessment (CE-POMA) with either a narrow (1-2 cm) or a wide (3-5 cm) margin.[5] However, because 3-5 cm margins are impractical for melanomas in cosmetically or functionally demanding sites, fewer than 1% of patients in these trials had melanomas on the head or neck, hands, feet, genitalia, and pretibial leg.[14] Thus, this data may not be generalizable to melanomas in these locations.

The NCCN guidelines provide two footnotes addressing melanomas on sites of cosmetic or functional importance. The first affords surgeons the ability to adjust margins to accommodate individual anatomic or practical considerations.[4] The second footnote states that for large in situ LM, surgical margins >0.5 cm may be necessary to achieve negative margins. Thus, techniques for the most exhaustive histologic assessment of margins should be considered.[4] These footnotes are ambiguous and defer the decision to the surgeon, whereas more established, definitive guidelines would arguably lead to better outcomes.

In a large prospective study, Kunishige et al.[15] found that a 12-mm margin was necessary to achieve 97% clearance of the margins for LM and MMIS on the head and neck. Thus they recommend at least a 9 mm margin of normal-appearing skin for these tumors. They also noted that on the head and neck and for tumors with a diameter of greater than 1 cm, even wider margins might be required thus they are best treated with MMS.[15]

Survival outcomes

Numerous authors have documented equivocal or improved survival with MMS compared to WLE for the treatment of invasive melanoma.[1],[6],[7],[16],[17],[18] Cheraghlou et al.[6] report a retrospective cohort study from the National Cancer Database, which included 70,319 patients, 67,085 of which were treated with WLE and 3,234 treated with MMS, with a modest improvement in overall survival in the MMS cohort relative to the WLE cohort, (hazard ratio [HR] 0.86, 95% confidence interval [CI],0.76-0.97; P = 0.02). Of note, the melanomas included in this study mainly were Breslow depth of <0.8 mm (64.2%), whereas 12.7% were 0.80-1.00 mm, and 23.1% were 1.01-2.00 mm.[6] Another retrospective cohort study sought to determine the optimal surgical management for melanoma on the head and neck.[7] A total of 50,397 patients with melanoma were included in the study, of which 7% were treated with MMS, and 93% were treated with WLE.[7] The study found that patients treated with MMS had significantly (P < .001) higher overall survival five years after diagnosis than those treated with WLE on univariate analysis.[7] However, this effect was no longer significant upon multivariate analysis[7] suggesting a possibly small group effect.

Breslow depth

Regarding Breslow depth, patients with melanomas of Breslow depth 0.01-0.74 mm had a statistically significant (P<.05) survival advantage when treated with MMS over WLE.[7] Regarding tumor histologic subtype, treatment of superficial spreading type, and LMM, MMS was associated with a statistically significant survival benefit compared to WLE.[7]

Melanoma on the face

For melanoma on the face, Trofymenko et al.[18] performed a retrospective review of 43,443 patients. They found that patients were much more likely to undergo narrow margin excision (NME, 57%) than WLE (27%) or MMS (14%). The overall 5-year risk of death was higher in the WLE and NME groups relative to MMS after adjusting for demographics, socioeconomic factors, and tumor characteristics.[18] The study found no statistically significant difference in melanoma-specific mortality between the groups.[18] These studies support the use of MMS for the treatment of melanoma with Breslow depth <0.8 mm on cosmetically and functionally demanding sites and histologic subtypes of superficial spreading and LMM on the head and neck.

Immunohistochemical stains

Initially, Mohs surgeons who performed MMS for melanoma were challenged to interpret slides with only hematoxylin and eosin stains on frozen sections. Since then, intraoperative immunohistochemical stains during MMS for melanoma have greatly improved the accuracy of margin assessment on frozen sections. Freeze artifact, tissue folding, and keratinocyte vacuolization resembling melanocytes present challenges in interpreting frozen section slides.[19] Additionally, some Mohs surgeons lack the training or experience to distinguish non-malignant melanocyte hyperplasia in chronically sun-damaged skin from MMIS.[19] The melanoma antigen recognized by T cells 1 (MART-1) immunostain highlights individual melanocytes, facilitating the detection of smaller foci of residual melanoma at surgical margins during MMS.[20] The sensitivity of MART-1 for primary cutaneous melanoma is nearly 100%, although it is not sensitive for spindle cell and desmoplastic melanomas.[21] Importantly, Cherpelis et al.[22] showed that frozen sections stained with MART-1 provide equivalent information to that obtained from MART-1 stained permanent sections, with the added benefit of examining 100% of the margins intraoperatively. Regarding patient outcomes, a retrospective cohort study of 2,144 melanomas excised using MMS and MART-1 demonstrated lower local recurrence rates and equivalent or higher survival rates than with WLE.[1] A large percentage of melanomas (82%) were excised with ≤6-mm margins,[1] highlighting the tissue-sparing advantage of MMS on cosmetically and functionally sensitive sites.

Although MART-1 immunostaining is sensitive,[23] lacks specificity on chronic sun-damaged skin.[24] This pitfall stems from MART-1 staining of “pseudomelanocytic nests,” or aggregates of cells and cell fragments, including keratinocytes, macrophages, and lymphocytes in the setting of lichenoid inflammation, leading to false-positive margins.[25],[26] Additional pitfalls of MART-1 immunostaining include poor staining for desmoplastic and spindle cell melanomas,[23] significant non-melanocyte epidermal staining leading to “false positives,” and difficulty with melanocyte density interpretation in chronically sun-damaged skin,[24] making a benign melanocytic proliferation difficult to distinguish from malignant melanoma. In contrast, the microphthalmia transcription factor (MITF) is a more specific immunostain, providing a clear outline of melanocyte nuclei.[24] In a study of 16 patients who underwent MMS for the treatment of MMIS or LMM, frozen sections were stained with MITF and MART-1 for comparison.[24] The mean melanocyte count (MMC) with MART-1 was significantly higher than with MITF on tumor-free, chronic sun-damaged skin, demonstrating that apparent melanocyte density is higher with MART-1.[24] More recently a melanocytic antigen nuclear marker, Sry-related HMG-Box gene 10 (SOX10) has been shown to more accurately represent true melanocyte density than MART-1.[27] However, SOX10 stains scars on frozen sections, further complicating interpretation.[27] Thus, the interpretation of dermal SOX10-positive cells should be further evaluated with hematoxylin and eosin.[27]


   Reappraisal Top


While according to NCCN guidelines WLE remains the standard of care for the treatment of invasive melanoma and MMIS, multiple studies support the superiority of MMS with immune staining in specific situations. In functionally and cosmetically demanding sites such as the head, neck, hands, feet, and pretibial leg where tissue conservation is essential, we recommend MMS for MMIS and all thin melanomas measuring <0.8 mm Breslow depth. Specifically, on the head and neck, all superficial spreading and LMM histologic subtypes <0.8 mm Breslow depth should be treated with MMS. Given the lack of consensus guidelines, the safety margin for MMS for MMIS varies among surgeons. The authors recommend starting with a >6 mm margin for the first MMS layer and continuing until negative margins are achieved. For LMM >0.8 mm Breslow depth should be referred to Surgical Oncology for consideration of sentinel lymph node biopsy. MART-1 is arguably the best immunostain to use intraoperatively given its high sensitivity, though MITF and/or SOX10 are useful for further clarification if necessary. For melanomas of a larger Breslow depth, studies have demonstrated non-inferiority of MMS as compared with WLE, but further studies should be conducted to confirm its superiority to WLE.

The benefits of using MMS with immunostains for melanoma include tissue sparing, comprehensive margin assessment, same-day surgery and reconstruction, and non-inferior survival and recurrence rates compared to WLE.

Limitations to this technique becoming more widely adopted include surgeons' and histotechnicians' lack of training or experience with the use of immunostains, compromised reliability in non-contiguous tumors, and uncertainty when microsatellites are identified.[19]Additionally, training in the use of MMS for melanoma is still not a widespread requirement for Mohs surgery fellowship programs further hindering progress toward standardization of this practice. The NCCN guidelines do not explicitly define the parameters for which MMS with intraoperative immunostains is appropriate; so many surgeons are hesitant to make this transition. Herein our reappraisal is based on the data available in the absence of strict guidelines. However, as MMS becomes more widely utilized for the treatment of melanoma, further studies examining long-term survival and recurrence rates after treatment should be conducted to confirm these trends. Overall, MMS with immunostains is a promising treatment modality for in situ and thin melanomas and has the potential to revolutionize the future care of melanoma patients.

Ethics committee/Institutional review board's permission

Not applicable.

Patient's consent

Not applicable.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Rzepecki AK, Hwang CD, Etzkorn JR, Shin TM, Sobanko JF, Howe NM, et al. The “Rule of 10s” versus the “Rule of 2s”: High complication rates after conventional excision with postoperative margin assessment of specialty site versus trunk and proximal extremity melanomas. J Am Acad Dermatol 2021;85:442-52.  Back to cited text no. 5
    
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Cheraghlou S, Christensen SR, Agogo GO, Girardi M. Comparison of survival after mohs micrographic surgery vs wide margin excision for early-stage invasive melanoma. JAMA Dermatol 2019;155:1252-9.  Back to cited text no. 6
    
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Hanson J, Demer A, Liszewski W, Foman N, Maher I. Improved overall survival of melanoma of the head and neck treated with Mohs micrographic surgery versus wide local excision. J Am Acad Dermatol 2020;82:149-55.  Back to cited text no. 7
    
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Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, Karakousis CP, 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;8:101-8.  Back to cited text no. 8
    
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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;89:1495-501.  Back to cited text no. 9
    
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Gillgren P, Drzewiecki K, Niin M, Gullestad HP, Hellborg H, Mansson-Brahme E, et al. 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: A randomized, multicenter trial. Lancet 2011;378:1635-42.  Back to cited text no. 10
    
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Khayat D, Rixe O, Martin G, Soubrane C, Banzet M, Bazex JA, et al. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer 2003;97:1941-6.  Back to cited text no. 11
    
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Thomas JM, Newton-Bishop J, A'Hern R, Coombes G, Timmons M, Evans J, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350:757-66.  Back to cited text no. 12
    
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Veronesi U, Cascinelli N. Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438-41.  Back to cited text no. 13
    
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Miller CJ, Giordano CN, Higgins HW 2nd. Mohsmicrographic surgery for melanoma: As use increases, so does the need for best practices. JAMA Dermatol 2019;155:1225-6.  Back to cited text no. 14
    
15.
Kunishige JH, Doan L, Brodland DG, Zitelli JA. Comparison of surgical margins for lentigomaligna versus melanoma in situ. J Am Acad Dermatol 2019;81:204-12.  Back to cited text no. 15
    
16.
Degesys CA, PowellHB, HsiaLB, Merritt BG. Outcomes for invasive melanomas treated with mohs micrographic surgery: A retrospective cohort study. Dermatol Surg 2019;45:223-8.  Back to cited text no. 16
    
17.
EliasML, Lambert WC. Surgical management of localized melanoma: A National Cancer Database retrospective review. Br J Dermatol 2019;181:832-3.  Back to cited text no. 17
    
18.
Trofymenko O, Bordeaux JS, Zeitouni NC. Melanoma of the face and Mohs micrographic surgery: Nationwide mortality data analysis. Dermatol Surg 2018;44:481-92.  Back to cited text no. 18
    
19.
Beaulieu D, Fathi R, Srivastava D, Nijhawan R. Current perspectives on Mohs micrographic surgery for melanoma. Clin Cosmet Investig Dermatol 2018;11:309-20.  Back to cited text no. 19
    
20.
Bricca GM, Brodland DG, Zitelli JA. Immunostaining melanoma frozen sections: The 1-hour protocol. Dermatol Surg 2004;30:403-8.  Back to cited text no. 20
    
21.
Busam KJ, Chen YT, Old LJ, Stockert E, Iversen K, Coplan KA, et al. Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg Pathol 1998;22:976-82.  Back to cited text no. 21
    
22.
Cherpelis BS, Moore R, Ladd S, Chen R, Glass LF. Comparison of MART-1 frozen sections to permanent sections using a rapid 19-minute protocol. Dermatol Surg 2009;35:207-13.  Back to cited text no. 22
    
23.
Albertini JG, Elston DM, Libow LF, Smith SB, Farley MF. 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;28:656-65.  Back to cited text no. 23
    
24.
Christensen KN, Hochwalt PC, Hocker TL, Roenigk RK, Brewer JD, Baum CL, et al. Comparison of MITF and Melan-A immunohistochemistry during mohs surgery for lentigomaligna-type melanoma in situ and lentigomaligna melanoma. Dermatol Surg 2016;42:167-75.  Back to cited text no. 24
    
25.
Beltraminelli H, Shabrawi-Caelen LE, Kerl H, Cerroni L. Melan-a-positive “pseudomelanocytic nests”: A pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin. Am J Dermatopathol 2009;31:305-8.  Back to cited text no. 25
    
26.
Maize JC Jr, Resneck JS Jr, Shapiro PE, McCalmont TH, LeBoit PE. Ducking stray “magic bullets”: A Melan-A alert. Am J Dermatopathol 2003;25:162-5.  Back to cited text no. 26
    
27.
Donaldson MR, Weber LA.SOX10 commonly stains scar in Mohs sections. Dermatol Online J2020;26:13030/qt0c04q1kc.  Back to cited text no. 27
    




 

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    Abstract
   Introduction
   Discussion
   Reappraisal
    References

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