Introduction

Mohs micrographic surgery (MMS), originally developed by Dr Frederic Mohs in the 1930s, is a technique designed to examine histologically 100% of the margins, peripheral and deep, of excised tissue. MMS has been extensively used and studied for the treatment of nonmelanoma skin cancer (NMSC), particularly at sites where tissue conservation is vital. The use of MMS for the treatment of melanoma has yet to become widely accepted owing to difficulties in histologic interpretation, among other factors. However, continued advances in MMS technique and immunohistochemical staining have allowed MMS for melanoma to gain further support.

Mohs first used this technique for treatment of melanoma in 1937, when it achieved fewer local recurrences and improved survival when compared with historical controls for standard excision. One contrasting feature between MMS and standard wide local excision is the minimization of sacrificed healthy tissue with similar or superior cure rates.

MMS can be performed on either fixed or fresh tissue. Working on fixed tissue was the first area explored by Mohs. In these cases, the tissue to be excised was fixed in place using a vehicle (zinc chloride paste), with each fixed plane being removed for histologic analysis. Issues with the paste (eg, pain, local inflammation, and lymphadenopathy) and the need to wait for the paste to penetrate and fix tissue in situ during successive excisions, requiring multiple-day visits, led to the development of fresh-tissue methods. These methods, lacking the fixative paste and usually requiring only a single session for the procedure, have become the predominantly employed form of MMS.

Rationale for use

Since MMS was first described and its use firmly established for treatment of NMSC, MMS has become an area of active interest for the treatment of melanoma. Lentigo maligna (LM) is a common subtype of melanoma in situ (MIS), comprising 79% to 83% of MIS, and it is especially prevalent in the white men aged 65 years and older. LM melanoma (LMM) is the invasive counterpart to LM and comprises 4% to 15% of cutaneous melanoma. Both LM and LMM present as irregular asymmetric pigmented patches on chronically sun-damaged skin. In these cases, margins can be difficult to ascertain, and in LMM, there may be extensive subclinical disease. Additionally, melanoma may occur on cosmetically sensitive areas of the head and neck and notably functional areas such as the eyelids, ears, nose, and perioral areas, where tissue conservation is of utmost importance.

Current excisional margin guidelines from the National Comprehensive Cancer Network are based on Breslow depth ( Table 1 ). Standard wide local excision for melanoma in situ is followed by histopathologic examination. Conventional transverse (bread-loaf) vertical sections require step-wise evaluation of the excision specimen, allowing histologic examination of only 0.1% of the total margin. This may result in false-negative margins and recurrence of melanoma. According to Kimyai-Asadi and colleagues, step sections at 1 mm, 2 mm, 4 mm, and 10 mm intervals would have a 58%, 37%, 19%, and 7% chance, respectively, of detecting positive margins. By their calculations, step sections would need to be performed every 0.1 mm to detect 100% of positive margins.

Several studies have shown that as melanoma approaches more closely to the margin on standard excision specimens, the local recurrence rate increases. The recurrence rate for melanoma in situ after wide local excision with standard 5 mm margins ranges from 8% to 20%. This may be due to presence of melanoma at the unexamined interval margins between step sections in wide excision specimens. When melanoma recurs due to residual disease, it may present with a more invasive component. Debloom and colleagues performed a prospective analysis on 108 marginally recurrent melanomas treated with standard excision or fresh-tissue MMS and permanent section of debulked specimens; 23% of patients with melanoma in situ left at the margin progressed to invasive disease, with a mean Breslow depth of 0.94 mm. Additionally, 33% of patients with minimally invasive melanoma left at the margin progressed to a greater depth of invasion with changes in mean Breslow depth from 1.5 mm at the time of primary treatment to 2.8 mm at the time of recurrence.

LM demonstrates a high rate of local recurrence of 9% to 20% after standard excision, which may occur more than 5 years after initial excision of the lesion. Osborne and colleagues showed that even with clear margins on standard histopathologic examination, local recurrence rate was 20%, and LMM developed in 1.5% of patients. Other case series showed local recurrence rates of about 9%.

Studies of MMS for LM have demonstrated significantly lower recurrence rates of 0.5% to 3%. Zitelli and colleagues studied 184 cases of melanoma in situ treated with fresh-tissue MMS, showing a local recurrence rate of 0.5%. Additionally, they treated 369 cases of invasive melanoma with fresh-tissue MMS, demonstrating a local recurrence rate of 0.5%. This was in contrast to local recurrence rates of 6% and 3% for in situ and invasive disease respectively after standard excisional surgery. They concluded that MMS is an effective treatment, especially in areas where tissue conservation is important. Bricca and colleagues studied 625 patients treated with frozen section MMS for primary cutaneous melanoma of the head and neck, demonstrating a local recurrence rate of 0.2% versus 9% or higher for standard surgery, with a mean follow-up of 58 months.

However, controversy remains regarding MMS in treating melanoma. The success of the procedure depends on both the ability of the surgeon to accurately detect melanoma at the excised margin with frozen sections and whether the margins narrow enough to excise the primary melanoma alone are adequate to prevent recurrence. Additionally, just as for MMS used for other neoplasms, the tumor growth pattern must be contiguous without skip areas.

Rationale for use

Since MMS was first described and its use firmly established for treatment of NMSC, MMS has become an area of active interest for the treatment of melanoma. Lentigo maligna (LM) is a common subtype of melanoma in situ (MIS), comprising 79% to 83% of MIS, and it is especially prevalent in the white men aged 65 years and older. LM melanoma (LMM) is the invasive counterpart to LM and comprises 4% to 15% of cutaneous melanoma. Both LM and LMM present as irregular asymmetric pigmented patches on chronically sun-damaged skin. In these cases, margins can be difficult to ascertain, and in LMM, there may be extensive subclinical disease. Additionally, melanoma may occur on cosmetically sensitive areas of the head and neck and notably functional areas such as the eyelids, ears, nose, and perioral areas, where tissue conservation is of utmost importance.

Current excisional margin guidelines from the National Comprehensive Cancer Network are based on Breslow depth ( Table 1 ). Standard wide local excision for melanoma in situ is followed by histopathologic examination. Conventional transverse (bread-loaf) vertical sections require step-wise evaluation of the excision specimen, allowing histologic examination of only 0.1% of the total margin. This may result in false-negative margins and recurrence of melanoma. According to Kimyai-Asadi and colleagues, step sections at 1 mm, 2 mm, 4 mm, and 10 mm intervals would have a 58%, 37%, 19%, and 7% chance, respectively, of detecting positive margins. By their calculations, step sections would need to be performed every 0.1 mm to detect 100% of positive margins.

Several studies have shown that as melanoma approaches more closely to the margin on standard excision specimens, the local recurrence rate increases. The recurrence rate for melanoma in situ after wide local excision with standard 5 mm margins ranges from 8% to 20%. This may be due to presence of melanoma at the unexamined interval margins between step sections in wide excision specimens. When melanoma recurs due to residual disease, it may present with a more invasive component. Debloom and colleagues performed a prospective analysis on 108 marginally recurrent melanomas treated with standard excision or fresh-tissue MMS and permanent section of debulked specimens; 23% of patients with melanoma in situ left at the margin progressed to invasive disease, with a mean Breslow depth of 0.94 mm. Additionally, 33% of patients with minimally invasive melanoma left at the margin progressed to a greater depth of invasion with changes in mean Breslow depth from 1.5 mm at the time of primary treatment to 2.8 mm at the time of recurrence.

LM demonstrates a high rate of local recurrence of 9% to 20% after standard excision, which may occur more than 5 years after initial excision of the lesion. Osborne and colleagues showed that even with clear margins on standard histopathologic examination, local recurrence rate was 20%, and LMM developed in 1.5% of patients. Other case series showed local recurrence rates of about 9%.

Studies of MMS for LM have demonstrated significantly lower recurrence rates of 0.5% to 3%. Zitelli and colleagues studied 184 cases of melanoma in situ treated with fresh-tissue MMS, showing a local recurrence rate of 0.5%. Additionally, they treated 369 cases of invasive melanoma with fresh-tissue MMS, demonstrating a local recurrence rate of 0.5%. This was in contrast to local recurrence rates of 6% and 3% for in situ and invasive disease respectively after standard excisional surgery. They concluded that MMS is an effective treatment, especially in areas where tissue conservation is important. Bricca and colleagues studied 625 patients treated with frozen section MMS for primary cutaneous melanoma of the head and neck, demonstrating a local recurrence rate of 0.2% versus 9% or higher for standard surgery, with a mean follow-up of 58 months.

However, controversy remains regarding MMS in treating melanoma. The success of the procedure depends on both the ability of the surgeon to accurately detect melanoma at the excised margin with frozen sections and whether the margins narrow enough to excise the primary melanoma alone are adequate to prevent recurrence. Additionally, just as for MMS used for other neoplasms, the tumor growth pattern must be contiguous without skip areas.

Fixed tissue surgical technique

Permanent section surgical technique combined with zinc chloride fixative paste (for ingredients, please see Table 2 ) is an excellent method for removal of invasive cutaneous melanoma. The procedure begins with a fresh-tissue biopsy of a suspected melanoma. A saucerized excisional biopsy is a preferred method, because this technique not only facilitates the removal of the suspected lesion, but also provides an ideal surface for the direct application of zinc chloride fixative paste once invasive melanoma has been histologically confirmed.

Permanent section biopsy results may be available as early as 1 day, but a delay of several days or more is not a problem. Zinc chloride fixative paste is very powerful. Its penetration can be deep, depending on contact time and thickness of application. It must not be applied until the diagnosis of invasive melanoma has been histologically confirmed. Bleeding may be stopped using direct pressure or aluminum chloride on a cotton-tipped applicator. Bleeding may also be controlled with the direct application of zinc chloride fixative paste and absorbable suture ligation, if necessary. The procedure is performed under local anesthesia. Analgesics are prescribed, but often are not necessary.

A dose of a pea size or less of zinc chloride paste is adequate for most melanomas. The paste is applied directly to the biopsy wound site extending to the epidermal edge with a cotton-tipped applicator to a total thickness of up to approximately 1 mm. If the lesion overlies an important anatomic structure, less may be applied; for thicker melanomas, more may be applied. The thicker the layer of paste applied, the more rapidly and deeper it penetrates.

The paste is held in place over the wound for a duration varying from 3 minutes to 24 hours after application. Much of the zinc chloride penetration occurs in the first few minutes, but zinc chloride continues to penetrate slowly over 18 to 24 hours, at which time it reaches its maximum depth of penetration. A complete and deep fixation of a biopsy site may occur in as little as 3 minutes with the paste held manually in place with a Telfa nonstick pad. For longer applications, a cotton ball covered with a commercially available transparent adhesive film can be used to hold the paste in place. In some cases, it may be convenient for the patient to return the following day before removing the dressing. When the dressing is removed, any remaining paste may be washed off with hydrogen peroxide or saline. If not done in the office, simple bathing at home with soap and water will have the same benefit. If the patient cannot return within a few days, he or she should be instructed to take any and all debris that comes off the site, place it in a plastic bag, and bring it to the office. Prolonged delays between paste application and excision of more than a week can result in spontaneous separation of the pasted tissue, and inadvertent specimen loss becomes a risk.

A wide local excision may be performed the same day as the paste application or may be delayed up to 1 week longer. Because zinc chloride fixative paste both kills and histologically fixes tissue, a conservative margin may be safely removed with no need to extend to the deep fascia. A saucerized excision using beveled Mohs margins, with mapping of the excised tissue specimens for permanent vertical or en-face sections, facilitates the wide local excision. If residual invasive melanoma is found, a delayed repeat excision may be performed.

The use of zinc chloride fixative paste (fixed-tissue micrographic surgery) has been shown by retrospective analysis to significantly improve overall 5-year survival compared with conventional surgery. Mohs reported a 30-year consecutive series of mostly advanced melanomas in which more than 1 out of every 5 patients treated with zinc chloride fixative paste had microscopically proven palpable regional lymph node metastases, and compared his results to simple primary melanomas treated by conventional surgery. Despite an expected far worse prognosis, 5-year survival was improved 53% in the melanomas treated with zinc chloride fixative paste. This result suggests that zinc chloride fixative paste may have an antimelanoma vaccine-like systemic effect.

To determine if zinc chloride fixative paste could act as an immune adjuvant, Kalish and colleagues performed a murine melanoma implantation study. Simple excision of implanted melanomas was compared with combined zinc chloride fixative paste and excision. Upon reimplantation of melanomas at a distant challenge site, 1 week after excision, there was a significant reduction of over 50% (69% vs 32%) in the development of new melanomas in the mice receiving the combined treatment. Most importantly, when poorly immunogenic melanomas were substituted in the experiment, this phenomenon did not occur, indicating that immune mechanisms were involved.

Additionally, there is 1 epidemiologic report suggesting that conventional surgery may spread melanoma. A data set of 1224 patients comparing the risk of metastases in thin melanomas within 1 year after surgery to the risk of metastases in thick melanomas before surgery indicated that surgical removal of primary melanoma may trigger metastatic dissemination or enhance growth of subclinical micrometastatic deposits, resulting in the development of clinically evident metastases. Warr and colleagues used a reverse transcriptase polymerase chain reaction (RT-PCR)-based assay to detect tyrosinase transcripts, a marker of occult melanoma cells, in peripheral blood during melanoma excisions. The study demonstrated that surgical intervention increased the presence of circulating tumor cells. The presence of tyrosinase transcripts in peripheral blood has been shown to be a useful marker of melanoma progression and poor prognosis. Several animal models have shown that surgical manipulation can trigger metastases of various cancers. However, the role of surgery as a contributing factor in the spread of melanoma metastases remains unknown. By killing tissue and stimulating immunity, zinc chloride fixative paste may help prevent the development of melanoma metastases.

Fresh-tissue surgical techniques

MMS for melanoma may be performed on fresh tissue under local anesthesia. According to 1 recent protocol, the first step is to mark the tumor’s clinical extent. The margin used is between 1 and 6 mm, depending on the location. For example, a smaller margin might be required when functionally important structures, such as tear ducts, are present, and tissue preservation is important.

Next, reference marks are placed at 12 o’clock, 3 o’clock, 6 o’clock, and 9 o’clock by making small nicks that overlap the visible tumor and perilesional skin. The clinically visible tumor is then excised/debulked, and a small (1 mm) central strip is removed from it. The central strip is then processed by frozen section to confirm the Breslow depth and to serve as a positive control against successive slides. The remainder of the surgical specimen is then submitted for processing of permanent sections and additional assessment of Breslow depth.

The first Mohs layer is then harvested using an incision along the previously marked margin. This incision is carried down to the desired depth of removal, but the horizontal incision of the deep margin is not performed yet. The epidermal and dermal portions of the Mohs layer are then removed together first, so as to be processed separately from the fat. This separation is important, because it allows for delicate 4 μm tissue sections needed for successful immunostaining. The strip itself is usually divided into 2 substrips, but more may be necessary if the tumor is large. Following the removal of the epidermal/dermal strip, the deep component of the specimen, consisting of the subcutaneous fat, is then excised parallel to the plane of the tissue surface.

All the excised tissue is then mapped relative to the reference marks, and the nonepidermal tissue is inked in 2 colors to facilitate mapping of the tumor. The specimen is oriented on a cold glass slide; embedding medium is applied, and then the specimen is adhered to a cryostat specimen object disc. Following this, the slide is warmed to separate it from the specimen, and the block is then cut at 4 μm step sections at intervals of 50 μm until all of the epidermis is visible. The slide is then stained with hematoxylin and eosin, and immunostains may be performed at this time as well. The surgeon analyzes the slides and marks any areas positive for tumor on the map. If any tumor is found, additional excision and processing stages are performed until the tumor is completely removed.

Challenges of MMS in the management of melanoma

The superior cure rates of MMS for melanoma depend on unequivocal evaluation of 100% of the surgical margins. This is only possible if the melanoma can be clearly discriminated from surrounding nonmalignant tissue. There are several concerns regarding the use of MMS for melanoma.

Challenges with Interpretation of Frozen Sections

There is significant challenge in identification of the pathologic changes of melanoma on frozen sections compared with atypical melanocytic hyperplasia in sun-damaged skin. Zitelli and colleagues noted sensitivity and specificity of 100% and 90%, respectively, of frozen sections for melanoma in a study comparing interpretations of 221 frozen and permanent sections. In this study, melanoma was defined as nests of atypical cells within the dermis or epidermis, or as atypical melanocytic hyperplasia. At the margin, single isolated atypical melanocytes were not identified as melanoma, because they are routinely found bordering benign lesions as well as actinically damaged skin. When scattered atypical melanocytes were scored as benign, 3 or more serial sections or deeper cuts required further examination. If the diagnosis of melanoma could not be unequivocally reached, the section was marked as positive to ensure re-excision. Areas of suspected regression of melanoma, defined as dermal melanophages, fibrosis, and lymphohistiocytic infiltrate, were also considered positive, although no melanoma was seen. Additionally, no attempt was made to distinguish between benign and malignant melanocytic lesions, resulting in excision of benign nevi at the margins.

In a study by Zitelli and colleagues, 535 primary cutaneous melanomas treated with MMS using frozen section stained with routine hematoxylin and eosin demonstrated excellent prognosis and a local recurrence rate of 0.5%. The study showed that 83% of melanomas were excised with a 6 mm margin, 95% with a 9 mm margin, and 97% with a 1.2 cm margin. Margin recommendations for complete excision for melanoma on the head and neck, comparing data by Zitelli and colleagues and the World Health Organization (WHO), are summarized in Table 3 . Greater margins were required for melanomas on the head/neck and acral areas, than on the trunk. Margin size was directly related to the clinical diameter of the melanoma. There was no significant relationship between required surgical margins and Breslow depth. Importantly, LM, with its typically large clinical diameter, was found to require greater than the recommended 5 mm margins to ensure complete removal. Additionally, because conventional excision relies on surgical margin width rather than clear histologic margins, a 9 mm margin is necessary for complete excision rate of 96.5%. Five-year survival and metastatic rates were comparable or favorable compared with wide local excision.

Table 3

Comparison of MMS margin recommendations to completely excise head and neck melanomas

Tumor Thickness	Zitelli	WHO
In situ	9 mm	5 mm
≤1.0 mm	9 mm	10 mm
1.01–2 mm	12 mm	10 mm
2.01–4 mm	12 mm	20 mm
>4 mm	>12 mm	20 mm

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