Surgical Management—Lentigo Maligna and Invasive Melanoma

5	Surgical Management—Lentigo Maligna and Invasive Melanoma Samuel Kim, Stephan Ariyan, and Deepak Narayan

LENTIGO MALIGNA

Introduction

Lentigo maligna (LM), otherwise known as Hutchinson’s melanotic freckle, is a subtype of melanoma in situ (MIS), accounting for 79% to 83% of MIS (1–3). It occurs most commonly on sun-exposed areas of the skin, particularly the head and neck (4). Incidence in the United States ranges from 0.6 to 0.8 cases per 100,000 and increases with age, peaking in the seventh and eighth decades of life (5–8). Histologically, atypical melanocytes develop at the dermal–epidermal junction with associated features such as bridging of the rete pegs, epidermal atrophy, extension of melanocytes down adnexal structures, and extensive solar elastosis (9–11). They may occur de novo or occasionally in association with a preexisting solar lentigo or melanotic nevus. LM typically grows slowly in a centrifugal or radial pattern with variable shades of tan, brown, dark brown, or black and can result in large diameters (Figure 5.1) (12).

Left untreated, however, these melanocytes can invade vertically into the dermis, becoming an invasive lentigo maligna melanoma (LMM) (1,2,9,13). Rarely, LM will progress rapidly to invasive disease (14,15). Because no longitudinal studies have been performed, the exact risk of progression of LM to LMM is unknown, but it is estimated to be anywhere between 5% and 50% based on epidemiologic data (13). Additionally, up to 16% of LM lesions will harbor invasive disease at the time of excision (16). LMM itself represents 4% to 15% of all melanomas and its prognosis is similar to that of other melanoma types, correlating with depth of invasion (2,9,13,17,18). Staging, like other melanomas, follows American Joint Committee on Cancer Guidelines.

Diagnosis

The diagnosis of LM by clinical examination alone is difficult due to its shared characteristics with other pigmented lesions, especially with the atypical (dysplastic) nevus. Both lesions can present as large macules, have irregular margins, be variegated in color, and have a background of erythema (Figure 5.1). Therefore, definitive diagnosis requires histopathologic evaluation. However, even this can prove challenging because both entities share histologic features of atypical melanocytic hyperplasia and require an experienced dermatopathologist to differentiate between the two diagnoses. Among the various biopsy techniques, excisional biopsy of the entire pigmented lesion down to the subcutaneous tissue is the most complete. However, large size and location may preclude a complete excisional biopsy (Figure 5.2). In these cases, a punch biopsy or multiple such biopsies of the darkest and most palpable areas is recommended (2,19). In our experience, shave biopsies are also adequate as long as they are deep enough to provide adequate information on the depth of the lesion. At the time of biopsy, invasive disease may be revealed, at which time the maximum depth of vertical tumor penetration can be measured and staged (Breslow depth, Clark level) to help guide surgical management (20,21).

Figure 5.1 An example of lentigo maligna (LM) roughly outlined with marker to approximate the lesion’s margins.

Operative Management

Complete surgical excision remains the treatment of choice for LM/LMM. In accordance with the National Institutes of Health (NIH) Consensus Conference on Melanoma in 1992, complete surgical excision of LM with 5-mm clinical margins is recommended as the standard of treatment (22). However, multiple studies have reported recurrence rates ranging from 8% to 20% of LM using the standard 5-mm margin. Significant subclinical involvement is thought to be the cause of this high recurrence rate (23–26). Also, the extent of sun damage to the melanocytes in this anatomic area makes it difficult to differentiate, by histology, severely damaged melanocytic hyperplasia/atypia from in situ melanoma. In light of these reports, the National Cancer Comprehensive Network in 2008 released guidelines indicating the likely limitations of 5-mm excisional margin for LM (27).

Figure 5.2 Another example of an LM on the sun-exposed area of a patient’s cheek. Note the macular surface, irregular borders, and variegation of color.

Since the original recommendations by the NIH were released, various surgical methods have been proposed to decrease recurrence such as staged surgical excision (SSE) and Mohs micrographic surgery (MMS). SSE is a surgical technique in which margins along the periphery of the lesion are excised and evaluated in stages until margin control is achieved. Johnson et al. described a type of SSE he termed the square procedure for LM/LMM excision (28). In this technique, the lesion is first outlined with the aid of a Wood’s lamp. Then, a surgical margin of 5 to 10 mm using a square or polygonal pattern is drawn around the lesion, and a 2- to 4-mm strip of tissue is excised around this margin. The resulting wound can be allowed to granulate or can be sutured closed, and the strips are sent for examination by the pathologist. The geometric configuration with angled corners of the excised strips is considered to facilitate tissue processing, orientation, and histopathologic examination. If positive margins are identified, repeat excisions of the positive margins are performed. Finally, the central lesion is excised after all margins are determined to be negative.

Since the original description of the square procedure, other techniques have also been described. The perimeter technique described by Mahoney et al. is very similar to the square procedure. Two-mm strips are excised around an initial 5-mm geometric margin (29). The contoured technique is like the squared technique but does not rely on sharp angles. This technique uses contoured excisions to preserve cosmetic units in anticipation of reconstruction (30). In the collerette technique proposed by Kassi et al., initial tumor edges are outlined using dermoscopy, and a 5-mm margin is drawn in a circular pattern using the numbers on a clock for positional reference (31). Then, a 2-mm strip of skin is excised from the margin edges. The surgical defect is closed, and the excised strips are divided into four segments and sent for histopathologic analysis. The procedure is repeated with another 5-mm margin beyond any positive segments until histopathologic analysis is negative, at which time the central primary lesion is excised. The spaghetti technique is identical to the collerette technique in terms of the margin distance and width of the strip excised. However, the tumor edges are delineated without dermoscopy and the margin is drawn in the shape of the primary lesion (15). All of these methods use paraffin-embedded permanent sections, which remain the preferred method of tissue processing and identification of histologic changes consistent with LM/LMM. Although these permanent sections can take considerable time to process, rush readings may be available and may be provided within 24 hours. Local recurrence rates for SSE as a whole range from 0% to 7.3% in the literature (20,25,28,29,32,33).

MMS is a particular type of tissue-conserving, staged surgical procedure in which histologic assessment of the surgical margin using horizontal (en face) frozen sections is used (34). The advantage of MMS over other types of SSE is the rapid turnaround in evaluation of these frozen sections compared with permanent sections. This enables complete excision during a single surgical procedure as opposed to multiple procedures in SSE. However, a frozen section is hampered by its decreased ability to assess for LM/LMM compared with permanent sections. Multiple studies have shown high discrepancy rates between frozen and permanent sections for positive tumor at the margins (35,36). Several variants of MMS have been introduced to overcome the limitations of frozen sections such as the incorporation of immunostaining at the time of frozen section evaluation. Other approaches include sending all final margins evaluated by frozen section for additional rush permanent section evaluation or processing all excised margins with rush permanent section (37–39). Local recurrence rates for MMS range from 0% to 33% in the literature (24,32,40–42). For these reasons, we do not recommend MMS with frozen sections at our institution.

Reconstruction

Various reconstructive methods have been described and are available to the patient, including primary repair, healing by secondary intention, skin grafts, local and regional flaps, and the free flaps (19). However, the type of reconstruction pursued depends on patient preference; location and size of the postexcision wound, patient comorbidities, and the quality of the surrounding skin all must be taken into consideration (Figure 5.3).

Nonoperative Management

Although complete surgical excision is the standard for LM/LMM treatment, factors such as location and size of the lesion and advanced age of the patient may limit the ability to obtain complete excisional margins or even make surgery unreasonable (13,43). Because of these factors, several nonoperative treatment methods have been explored such as cryotherapy, laser ablation, curettage, radiation therapy (RT), and topical immunotherapy. Overall, all these nonoperative methods have higher recurrence rates than surgical excision on long-term follow-up (44). However, they may still be considered for a subset of patients with particular circumstances such as: elderly patients who are unsuitable for surgery, patients with lesions that involve unresectable regions of the face, and patients with extensive lesions where surgical intervention would lead to poor cosmetic outcome.

Figure 5.3 (A) A patient presenting with LM on the right cheek. (B) The lesion’s borders are delineated and an approximate 5-mm margin is outlined around the lesion, taking into account the lesion’s anatomic location. (C) Further markings are drawn to plan for a primary closure after excision of the lesion. (D) Primary closure of the defect after lesion excision is shown to be healing appropriately.

There is growing research evaluating the use of these nonoperative modalities in conjunction with surgical excision, particularly with the use of the topical immunotherapy agent imiquimod (45–50). The evidence of imiquimod’s efficacy has led to the National Comprehensive Cancer Network’s (NCCN) Clinical Practice Guidelines in Oncology for melanoma to include consideration for imiquimod as a treatment option for selected patients with positive MIS margins after surgery (27). Imiquimod exhibits antitumoral activity by inhibiting angiogenesis and increasing peritumoral infiltration of natural killer cells and cytotoxic T cells, resulting in death of melanoma cells. Additionally, imiquimod activates macrophages and other immune cells via binding to the cell-surface receptor, Toll-like receptor 7, and causes the release of proinflammatory cytokines such as IFN-α, TNF-α, and IL-12 (51–53). A recent review of our experience studying the efficacy of topical imiquimod treatment for the management of positive in situ margins after initial surgical excision of MIS showed a 95% complete resolution confirmed by multiple punch biopsies during a mean follow-up period of 24 months; this was comparable to complete surgical excision alone as published in the literature (45).

Recommendations

After histologic diagnosis of LM by biopsy, we recommend delineation of the lesion’s borders with the assistance of ultraviolet light. The recommendations are surgical excision of the entirety of the lesion with 5-mm margins, but we will excise up to 1-cm margins depending on the surrounding facial structures (Figure 5.2). For positive histologic margins after initial excision, we advocate reexcision of another 5 mm along the positive margin(s).

If the patient decides to undergo reexcision, reconstruction can be performed after achieving complete histologic control of the margins. For those patients found to have positive excision margins and who do not desire to undergo further surgery, we recommend topical imiquimod therapy for 5 days a week for 12 weeks. The frequency of the treatment regimen may need to be individually tailored to the patient based on each individual’s clinical response or tolerance to the therapy. The common side effects of using topical imiquimod include burning, pain, tenderness, vesicular eruptions, and ulcerations; these will subside after discontinuation of therapy. In fact, the degree of inflammation on and around the site of treatment may be used as an indicator of treatment response and a positive predictor of outcome (48,54). Other, rare side effects have been reported such as pigmentary changes (e.g., vitiligo or hyperpigmentation), chronic neuropathic pain, and angioedema (55–57). After the treatment period has ended, it is our practice to excise an entire 1-mm strip along the previously positive margin(s) at 8 weeks after the last application of topical imiquimod (allowing adequate time for the inflammation to resolve) to confirm the adequacy of the treatment. Persistent positive margins will require surgical reexcision. In patients who pursue topical imiquimod therapy and do not develop an inflammatory response, tazarotene may be added to the topical treatment. Hyde et al. reported that tazarotene may help to increase the penetration of topical imiquimod by disrupting the stratum layer of the skin (58). In a prospective randomized trial, patients treated with a combination of imiquimod and tazarotene had significantly higher grade inflammatory responses than those patients receiving imiquimod alone. There was a trend toward higher complete response rates in the combination therapy group, but results were not statistically significant. Further research on imiquimod and tazarotene combination therapy is required.

MALIGNANT MELANOMA

Introduction

Malignant melanoma is the fastest growing cancer in the United States today, with incidence rates doubling from 1982 to 2011 (59). It is currently the fifth and sixth most common cancer in males and females, respectively (60). There were approximately 76,100 new diagnoses of melanoma and 9,710 deaths from melanoma in 2014 (61). Although these numbers may be cause for concern for newly diagnosed patients, melanoma, overall, compares favorably against many other types of cancer with 5-year survival rates approaching 90% (60). Our knowledge of the genetics and behavior of melanoma continues to grow, and our choices of drug therapy continue to expand. However, despite these advances, surgery continues to be the most effective treatment for this disease. Proper planning, excision, and subsequent reconstruction will provide the patient with the best chance for disease-free survival while maintaining anatomic form and function.

Biopsy

A biopsy of the suspected lesion and histopathologic examination are necessary for definitive diagnosis and subsequent surgical planning. Prior concerns over the safety of biopsying a melanoma with possible hematologic dissemination of tumor cells have been found unjustified by several studies, which demonstrated the safety of biopsies before surgical excision (62–64). A variety of biopsy techniques for diagnosis are at the physician’s disposal including excisional, incisional, punch, and shave biopsy techniques. Our preferred method is an excisional biopsy with 1- to 2-mm margins around the lesion. Care should be taken to orient the biopsy for possible wider excision should further surgical excision be needed. The suspected lesions will sometimes be very large in size or present functional and/or cosmetic concerns. In these instances, an incisional or punch biopsy is an acceptable option. Lederman and Sober (65), on reporting their prospective study of 472 patients with melanoma, stated that excisional and incisional biopsy methods were both appropriate for diagnosing melanoma and had no differences in survival rates. Shave biopsies are generally not recommended for diagnosis due to concerns over obtaining proper skin depth that would give important prognostic information to further guide management. In all cases, biopsies should be read by an experienced dermatopathologist who will provide the surgeon with histopathologic features of the melanoma that will help guide surgical management (e.g., Breslow thickness, Clark level, ulceration, and mitotic rate).

Margins of Excision

In Handley’s original descriptions of the excision of melanoma in 1907, 5-cm margins around the melanoma were recommended for complete removal and prevention of recurrence (66). Since then, multiple studies have tested more conservative margins and their impact on local recurrence and survival. They have gradually modified Handley’s original recommendation in favor of smaller margins. For example, Breslow and Macht found that for melanomas with thickness of up to 2 mm, recurrence rates were not significantly different between 1-cm and 3-cm surgical margins (67). They advocated a more conservative surgical margin, especially for thinner melanomas. Similarly, Balch et al. did not find a significant difference between 2-cm and 3-cm margins for intermediate-thickness melanomas (1–4 mm) (68). Finally, Ringborg et al., in a prospective of 769 patients with melanomas 0.8 to 2 mm in thickness, did not show a significant difference between 2-cm and 5-cm surgical margins (69). While melanoma thickness is the most important factor in determining surgical margins for resection, studies such as these show that more conservative margins have become the standard of care. Smaller margins decrease the morbidity of surgery, conserve function, and simplify reconstruction, all while maintaining comparable survival rates. We currently follow the NCCN Guidelines that recommend margins of excision based on Breslow thickness (70).