Summary: Introduction

¥Incidence and mortality of cutaneous melanoma continue to rise, despite improvements in diagnosis of early stage disease.

¥Surgical excision of primary invasive melanoma is presently the only effective treatment and is the standard of care for melanomas of all depths.

¥While early stage melanoma is highly curable with surgery, advanced stage melanoma is relatively resistant to conventional therapeutic regimens and is often fatal.

18.1Introduction

Malignant melanoma represents the most deadly form of skin cancer [1]. Its incidence and mortality rates have risen steadily across all age groups since at least the middle of the twentieth century [1]. Current estimates indicate that its incidence is increasing at a rate of 5% per year [1]. It is anticipated that the lifetime risk of developing melanoma in the United States is now between 1 in 75 and 1 in 39, versus 1 in 1,500 in 1935 [1, 2]. In spite of signiÞcant improvements in diagnosis of early stage disease [3], the mortality rate for melanoma has been continually increasing over the past decade, and the disease represents one of the most common fatal malignancies of young adults [1]. While early stage melanoma is highly curable with surgery [4], advanced stage melanoma is relatively resistant to conventional therapeutic regimens and is often fatal [5Ð7]. Although promising results have been obtained with B-Raf and MEK inhibitors in recent clinical trials [8Ð10], the lack of effective conventional therapies for the treatment of advanced stage disease has stimulated interest in the application of novel strategies for the treatment of patients with malignant melanoma. Nonetheless, clinical trials have failed to reproduce the therapeutic beneÞt shown in animal models [11Ð16]. To date, surgical excision of primary invasive melanoma is the only effective treatment and is the standard of care for melanomas of all depths [17Ð20].

In this chapter, we will Þrst review the current recommendations for the surgical treatment of melanoma as well as their associated pitfalls. Second, we will discuss the role of Mohs micrographic surgery (MMS) in

the surgical treatment of melanoma including the different techniques utilized, the use of frozen versus formalin-Þxed tissue as well as the advantages and disadvantages of the available immunohistochemical (IHC) stains. Third, we will discuss the long-term clinical responses in patients with melanoma treated with MMS. Lastly, we will discuss potential strategies to improve the surgical treatment of melanoma.

Summary: Surgical Treatment of Melanoma

¥The goal of surgical treatment of melanoma is complete removal of the primary tumor.

¥Recommended surgical margins are largely based on consensus.

¥Melanomas are clinically and biologically diverse, and therefore reliable standardized margins do not exist to guide the surgeon in every case.

18.2Surgical Treatment of Melanoma

Surgical excision of primary invasive melanoma is the standard of care of all depths [17Ð20]. The goal of surgical treatment for cutaneous melanoma is complete removal of the primary tumor. Complete removal of the primary tumor prior to metastasis eliminates the chance for local recurrence, nodal metastasis, distant metastasis, and death from melanoma. Although the recommended margins for standard excision are well recognized (Table 18.1), they continue to remain a source of some controversy. Until recently, margins of 5 cm or more were standard, but these were based more on personal bias and surgical dogma than scientiÞc evidence. It was not until Clark et al. [21] and Breslow [22] established that level and thickness of the primary melanoma could be used to predict the prognosis accurately that groups of patients with a similar prognosis could be collected to compare the outcome

Table 18.1 Recommended surgical margins for excision of primary cutaneous melanoma

of different surgical margins. To date, only Þve prospective randomized studies have been conducted to investigate surgical excision margins for primary cutaneous melanoma [23Ð28]. These studies have failed to show any difference in overall survival in patients with tumors of various thickness treated with narrow (1Ð2 cm) versus wide (3Ð5 cm) surgical margins. Although todayÕs standards for excision of primary cutaneous melanoma are somewhat based on the results of the aforementioned trials, it must be stressed that the current guidelines continue to be largely based on consensus recommendations [29, 30]. It is key for the dermatologic surgeon to recognize that there is no evidence to demonstrate that todayÕs standards for excision of primary cutaneous melanoma are superior to the narrowest margin that removes the tumor in its entirety. The ability to remove a tumor in its entirety utilizing the narrowest surgical margins reßects the aim of MMS.

Many surgeons continue to rely on the excision of wide margins of normal skin because of the possibility that these wider margins may contain micrometastases with the assumption that removal of micrometastases will limit recurrences and improve survival. There is no evidence to support these claims. The presence of micrometastases within surgically excised primary cutaneous melanomas is statistically associated with disease-free survival [31], and those patients have a prognosis similar to that of patients with known in transit or nodal metastatic disease [32Ð37]. These Þndings suggest that micrometastases are merely indicators of distant metastatic disease. Therefore, wider surgical margins are unable to remove all metastatic disease. Again, it must be stressed that the available evidence suggests that narrower margins are as good as wider margins in the excision of primary cutaneous melanoma with no difference in overall survival [29, 30]. Taken together the available evidence supports the notion that the distance of the margin of excision from the edge of the tumor is immaterial as long as the tumor has not metastasized and is removed in its entirety.

Melanomas are clinically and biologically diverse, and therefore reliable standardized margins do not exist to guide the surgeon in every case. There is particularly limited data to provide guidelines for the treatment of (1) melanomas more than 4 mm thick; (2) melanomas on the head, neck, hands, feet, and genitals; and (3) in situ melanomas. Moreover, while there

is some evidence supporting the current guidelines for width of excision of primary cutaneous melanoma, there is a paucity of data supporting the appropriate depth of excision [38Ð40]. In 1992, a National Institutes of Health (NIH) Consensus Panel suggested that MIS be excised to subcutaneous tissue while invasive melanoma should be excised to fascia [41]. However, these recommendations regarding depth of excision have been based only on the personal opinions of the panel members. To the best of our knowledge, there is no clinical evidence to support or refute the current depth of excision recommendations. Current guidelines, including those of the National Comprehensive Cancer Network (NCCN) Melanoma Panel [42], the British Association of Dermatologists [43], and the American Academy of Dermatology (AAD) Guidelines/ Outcomes Committee [44], do not make recommendations with regard to depth of excision. The NIH Consensus Panel has stated that the recommendation of excision of invasive melanomas to fascia is Òbased on the anatomic understanding that the lymphatics drain to the regional lymph nodes in the subcutaneous tissue extending to the underlying muscle fasciaÓ [45]. Nevertheless, to the best of our knowledge, there is currently no sound scientiÞc evidence for or against excision of melanoma to the fascia.

The only ÒcorrectÓ surgical margin is that which removes the entire tumor and conserves the most normal tissue. It is paramount to understand that melanomas often have indistinct clinical margins and may be amelanotic at the periphery, making proper surgical planning difÞcult. Furthermore, melanomas of the head and neck, which represent 17Ð25% of all melanomas [46], as well as those on the hands, feet, and genitals often exist near vital structures that compromise the ability to excise the standard margins without causing serious functional or cosmetic deformities. Oneto two-centimeter margins in these locations are generally impractical and strongly favor the most tissue conservative approach in the excision of the tumor. Moreover, local recurrence rates on the head, neck, hands, feet, and genitals range from 9% to 20% with standard excisional margins, far higher than the 3% rate reported on the trunk [47Ð51]. Given these high recurrence rates, some have suggested amputation as surgical treatment of cutaneous melanoma in areas such as the hands and feet [52, 53].

The local recurrence rates on the head, neck, hands, feet, and genitals may reßect both technical as well as

biologic variables. From a biologic viewpoint, this high recurrence rate may reßect the ability of melanomas to grow with invisible subclinical extensions analogous to other cutaneous malignancies. As will be discussed below, these extensions may be missed by conventional histopathologic examination of excised tissue. Although melanin pigment helps to deÞne the margins for melanomas, pigment is not always present and is least visible in nests of tumor cells at the periphery. In areas of chronic sun damage such as the head and neck, these extensions are often camoußaged by ephelides, pigmented actinic keratoses, lentigines, nevi, seborrheic keratoses, or thick stratum corneum. Lastly, unique anatomic features of the hands and feet include the nail plate and nail fold, which often make determining the clinical margins of melanoma difÞcult.

From a technical viewpoint, some surgeons may be more conservative with their surgical margins and not adhere to established standards in areas such as the head, neck, hands, feet, and genitals. This is due to the problems associated with radical excision in these cosmetically and functionally sensitive areas. Further, it must be stressed that conventional histopathologic evaluation of surgically removed tissue using vertical sectioning lacks the ability to completely identify tumor margins. SpeciÞcally, when excisional specimens are sent to the pathology laboratory to check the margins for residual tumor, serial thin sections are cut from the tissue perpendicular to the epidermis. Representative vertical sections are often taken at 2Ð4 mm intervals throughout the tissue specimen. For a well-deÞned tumor, this may sufÞce, but the 2Ð4 mm between sections is not examined. A tumor determined to have clear margins by this bread loaf method may, in fact, have extensions of tumor in the unexamined intervals, as <1% of the margins are actually visualized [54]. Therefore, conventional histopathologic examination of the tumor margin is more likely to lead to false negative margin assessment and may be an explanation for a higher marginal recurrence rate after a tumors Òcomplete excision.Ó Whatever the reason for the high rate of local recurrence of melanomas on the head, neck, hands, feet, and genitals, it is important to realize that failure to completely remove a primary melanoma surgically has important clinical consequences. Tumors recurring after incomplete excision often are of increased BreslowÕs depth, one of the most important predictors of survival in patients with cutaneous melanoma [55].

Summary: MMS for Cutaneous Melanoma

¥Evidence supports the notion that the distance of the margin of excision from the edge of the tumor is immaterial as long as the tumor is removed in its entirety.

¥Microscopic margin control eliminates the problem of indistinct clinical margins seen in photodamaged skin and conserves normal tissue.

¥Up to 8% of primary cutaneous melanomas surgically treated with the current recommended NIH guidelines are inadequately excised.

18.3MMS for Cutaneous Melanoma

As discussed above, the available evidence suggests that wide margins do not improve survival or decrease the risk of satellite metastases when compared with more narrow margins as long as the primary melanoma is completely excised [29, 30]. MMS uses the microscope to allow for histologic examination of 100% of the peripheral tumor margin in a three-dimensional fashion. Microscopic margin control eliminates the problem of indistinct clinical margins seen in photodamaged skin and conserves normal tissue, thereby minimizing functional and cosmetic disÞgurement. As will be discussed below, the use of MMS in combination with the IHC technique (Fig. 18.1) has greatly expanded our capacity to treat a wide array of malignancies using MMS, especially melanoma. The use of MMS to determine surgical margins is not unique to primary cutaneous melanoma since MMS has been used to measure the difference between the clinical diameter and the subclinical diameter of other skin cancers to establish guidelines for excisional margins for basal cell carcinoma, squamous cell carcinoma, dermatoÞbrosarcoma protuberans, and recurrent cutaneous melanomas [56Ð59]. In primary cutaneous melanoma, local recurrence as well as overall cure rates of patients with melanoma treated with MMS is at least as good as surgery with standard wide surgical excision margins [46, 60Ð66]. Zitelli et al. have reported statistically signiÞcant decreased local recurrence rates at 5 years in patients treated with MMS compared to historical controls treated with wide local excision [46, 66]. In these studies, the 5-year local recurrence rates for MIS and invasive melanoma were between 0% and 0.5% [46, 66]. Bricca et al. have expanded these studies demonstrating that patients with mela-