Mohs Micrographic Surgery for Lentigo Maligna and Lentigo Maligna Melanoma Using Mel-5 Immunostaining: An Update from the University of Minnesota JESSICA NEWMAN, MD, MATTHEW BEAL, MD, SARAH E. SCHRAM, MD, AND PETER K. LEE, MD, PHD*

BACKGROUND Mohs micrographic surgery (MMS) is gaining acceptance as a treatment for lentigo maligna (LM) and lentigo maligna melanoma (LMM), especially with the use of melanocyte-staining immunohistochemical (IHC) stains. In 2006, we reported our 4-year experience with Mel-5 immunostaining, with only one recurrence noted in 200 patients after a mean follow-up of 38.4 months.1 OBJECTIVES

We present an update regarding our 13-year experience with the use of Mel-5.

METHODS AND MATERIALS Patients with primary or recurrent LM or LMM (n = 260) underwent MMS with Mel-5; 174 were followed up to evaluate for recurrence, with a mean follow-up of 34 months. The 200 patients described in the initial case series from 1999 to 2003 were also followed. RESULTS Of the 460 patients treated from January 1999 to December 2011, five recurrences were noted in four patients; one in the initial case series and four in this new, updated series, including one re-recurrence from the initial series. One melanoma-related death occurred in a patient intermittently lost to follow-up. CONCLUSION and LMM.

MMS with Mel-5 immunostaining continues to yield excellent results in the treatment of LM

The authors have indicated no significant interest with commercial supporters.

L

entigo maligna (LM), a subtype of melanoma in situ arising on sun-damaged skin, is characterized by extensive subclinical horizontal spread and has been historically difficult to cure with standard 5-mm surgical margins.2 Untreated, it may progress to invasive lentigo maligna melanoma (LMM). The use of Mohs micrographic surgery (MMS) in the treatment of melanoma significantly reduces the recurrence rate3 by increasing the histologic clearance rate, while also minimizing tissue loss. Multiple IHC stains have been employed to delineate melanocytes on frozen section, including HMB-45, S-100, melanoma antigen recognized by T-cells 1 (MART-1; also known as Melan-A), microphthalmia-associated transcription factor (MiTF), and Mel-5.1,4–6

The need for improvement over the historically recommended 5-mm margins for LM is clear. Osborne and Hutchinson reported 9% incomplete excision of LM with this technique and 20% recurrence at 42 months in lesions reported to be excised.2 Kunishige and colleagues7 used MMS to refute the standard 5-mm margins for melanoma in situ. In a large study of 1,120 tumors treated with consecutive 3-mm margins, only 86% were completely excised at 6 mm, whereas 98.9% were removed at 9 mm. The recurrence rate was 0.3% at 5 years using MMS with hematoxylin and eosin (H&E), compared with 8 to 20% using 5-mm margins in various other studies.7

*All authors are affiliated with Dermatology Department, University of Minnesota, Minneapolis, Minnesota © 2013 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc.  ISSN: 1076-0512  Dermatol Surg 2013;39:1794–1799  DOI: 10.1111/dsu.12356 1794

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In response to the concern that atypical melanocytes cannot be adequately identified on frozen section, Bene and colleagues8 found that the negative margins identified on MMS frozen section were concordant with the criterion standard, permanent section, in 95.1% of cases. These data were specifically collected from 116 patients with LM. In 1997, Zitelli and colleagues3 reported a 0.5% 5-year recurrence rate with MMS for melanoma and melanoma in situ. Various other techniques have been described, including “slow-Mohs” with overnight rush permanent sections9,10 and “the spaghetti technique”.11 We prefer MMS for the convenience, safety, and comfort of same-day closure, as well as the ability to evaluate all margins fully and ensure histologic clearance. Immunohistochemical stains aid in these various methods by highlighting melanocytes. Kim and colleagues5 compared melanocyte densities determined using four IHC stains with H&E in 20 cases of melanoma in situ. They found that staining with HMB-45 and MiTF produced similar results to H&E, whereas MART-1 overestimated and Mel-5 underestimated melanocyte counts. Various laboratories have reported rapid protocols to decrease the time that IHC staining adds. Cherpelis and colleagues4 demonstrated a rapid 19-minute protocol for staining frozen sections with MART-1 with similar efficacy to MART-1 permanent sections, and Kimyai-Asadi and colleagues12 described a 20-minute protocol that was as effective as their hour-long protocol. Glass and colleagues6 have described a 35-minute protocol for the nuclear stain MiTF. Unlike MART-1, MiTF does not stain dendritic processes of out-of-plane melanocytes, resulting in a more-accurate count. MiTF also measures nuclear diameter, a marker of atypia, equally well in frozen and permanent sections. The authors prefer the use of both stains together.6

Many laboratories use the cytoplasmic stain MART1 for its reported usefulness in detecting individual melanocytes12 and for its diminished background staining in comparison with the melanosome-staining Mel-5, which also stains basal cells of the epidermis.13 Despite these findings, in our laboratory, we have tried MART-1 and Mel-5 and found greater success and minimal collateral staining of nonmelanocytes using Mel-5 (Figure 1). Other authors have described problems with MART-1, including the potential to overestimate the number of melanocytes5 and stain “pseudomelanocytic nests” consisting of keratinocytes, melanocytes, and inflammatory cells in what is truly a lichenoid dermatitis on the background of sun-damaged skin.14 Based on the low recurrence rate using Mel-5 at our institution published by Bhardwaj and colleagues1 in 2006, we have continued to use Mel-5. At that time, we reported a 99.5% cure rate in 200 patients treated for LM or LMM with MMS using Mel-5, with no melanoma-attributed deaths in a mean 38.4 months of follow-up. Staining with Mel-5 added 41 minutes of processing time and allowed for clearer delineation of melanocytes than with H&E. Here we present our now 13-year experience using MMS with Mel-5 for LM and LMM, including follow-up from the previous study population.

Materials and Methods Patients with primary or recurrent LM or LMM (n = 260) were treated using MMS from January 2004 to December 2011 at the Dermatology Department at the University of Minnesota. Institutional review board approval for this retrospective chart review was obtained. All tumors were biopsy proven and classified as primary, recurrent, or incompletely excised based on whether they had undergone diagnostic biopsy alone, excisional surgery with negative histopathologic margins and subsequent biopsy-proven recurrence at the same site, or excisional surgery with positive histopathologic margins. Patients with tumors with Breslow

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(A)

(B)

(C)

(D)

(E)

(F)

Figure 1. Left column represents staining with hematoxylin and eosin; right column represents staining with Mel-5. Examples of positive controls at 920 magnification (A and B), positive margins at 910 (C and D), and negative margins at 910 (E and F) from cases of lentigo maligna. Note lack of background staining on negative control slide.

depth >0.75, ulceration, or aggressive histologic features were offered sentinel lymph node biopsy, total lymph node dissection, or partial parotidectomy as indicated. One hundred seventy-four of the 260 patients and the original 200 patients were followed up to evaluate for recurrence. Information about recurrence was obtained whenever feasible for patients with follow up outside of our system. Histopathologic Definitions Lentigo maligna was defined as contiguous atypical or pleomorphic melanocytes along the basal layer or appendageal spread of melanocytes in areas of

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dermal solar elastosis. LMM was defined as LM plus atypical melanocytes within the dermis. Positive margins were defined as five or more atypical or pleomorphic melanocytes arranged in runs, clusters, or nests along the basal layer or as any melanocytes above the basal layer or within the dermis. Any confluences of atypical or pleomorphic melanocytes were also compared with the histopathologic features of the primary tumor as observed in the positive control obtained from the debulk specimen. Small aggregates of atypical melanocytes (

Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma using Mel-5 immunostaining: an update from the University of Minnesota.

Mohs micrographic surgery (MMS) is gaining acceptance as a treatment for lentigo maligna (LM) and lentigo maligna melanoma (LMM), especially with the ...
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