Mohs' micrographic surgery for the treatment of melanoma

Dermatol Clin 20 (2002) 701 – 708

Mohs’ micrographic surgery for the treatment of melanoma John A. Carucci, MD, PhD Chief, Mohs Micrographic and Dermatologic Surgery, Department of Dermatology, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA

The incidence of melanoma continues to rise with approximately 50,000 diagnosed annually in the United States [1]. It is estimated that 1 in 70 Americans will develop melanoma [2]. Although the trend is toward earlier diagnosis of thinner melanomas, the mortality rate from melanoma continues to be significant [3]. Standard surgical excision with clear margins remains the treatment of choice [3]; however, the use of Mohs’ micrographic surgery (MMS) for melanoma continues to gain popularity [4]. This article focuses on the basis of MMS as a treatment option for melanoma by examination of tumor biology, standard surgical excision margins, and the Mohs’ method; interpretation of melanoma on frozen sections; and the use of special stains to increase the specificity of detection of melanoma.

Biologic behavior of melanoma Melanoma is a life-threatening cancer of melanocytes with the potential to metastasize to regional lymph nodes and distant organs including liver, bone, and brain [5]. Prognosis is proportional to Breslow depth (Table 1) [6]. Melanoma in situ has an excellent prognosis and a high cure rate after excision. Melanomas less than 0.76 mm are considered thin and carry an overall better prognosis than melanomas greater than 0.76 mm in depth. Lentigo maligna (LM), an indolent subtype of melanoma in situ that occurs on sun-damaged areas of the head and neck, may progress to invasive LM melanoma [7]. Because of the potentially aggressive nature of melanoma,

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surgical excision with appropriate clear margins is the treatment of choice. Appropriate margins of excision have decreased throughout the twentieth century and the trend toward narrow margins continues today [8]. One of the paramount biologic questions in melanoma management is whether excision of the primary cancer is sufficient for cure. If so, then narrow clear margins should be sufficient for cure. If not, then wide margins might be required as originally thought, to decrease the potential for undetectable microscopic foci of tumor cells to persist and metastasize. This is not necessarily supported by the fact that findings of in-transit metastatic disease on excision results in poorer prognosis with higher risk of widespread metastatic disease [9]. In one study, primary melanomas greater than 1.5 cm with microscopic metastases were associated with nodal metastases more often than melanomas of similar thickness without satellites (53% versus 12%) [9]. Satellites were defined as nests of melanoma greater than 0.05 mm in the reticular dermis, panniculus, or vessels beyond the principal tumor but separated by normal tissue.

Treatment of primary melanoma Standard excision and margins Excision margins for melanoma range from narrow (0.5 cm) for melanoma in situ to 2 cm for lesions greater than 2 mm in Breslow depth (Table 2) [8]. The concept of wide local excision is based on the idea that excision of the cancer alone is not sufficient for cure. Wide margins are taken to excise any otherwise undetected micrometastatic disease; how-

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Table 1 Prognosis based on melanoma depth Depth of invasion (mm)

5-year Survival (%)

< 0.76 0.76 – 1.49 1.50 – 2.49 2.50 – 3.99 > 4.0

96 87 75 66 47

ever, the presence of satellite metastases has been associated with an increase in regional disease even when completely excised [9]. Clarification of margin assessment of standard excision specimens is necessary. Margins are assessed from representative sections of the specimen in ‘‘bread loaf’’ fashion allowing only sampling of the specimen [10]. This degree of examination may occasionally result in a false-negative assessment of clear margins in cases of infiltrating, or aggressive growth cancers. Similar misdiagnosis may result when vertically cut frozen specimens are relied on for intraoperative margin control.

Mohs’ micrographic surgery Mohs micrographic surgery facilitates optimal margin control and conservation of normal tissue in the management of nonmelanoma skin cancer [11 – 13]. Dermatologic surgeons specially trained in the technique perform MMS in an office setting under local anesthesia. Briefly, a tangential specimen of tumor with a minimal margin of clinically normalappearing tissue is obtained, precisely mapped, and processed immediately by frozen section for microscopic examination (Fig. 1). Optimal margin control is obtained by examination of the entire perimeter of the specimen and contiguous deep margin. Meticulous mapping allows for directed extirpation of any remaining tumor. A key defining feature of

Table 2 Standard excision margins based on melanoma depth Depth of invasion (mm)

Standard excision margins (cm)

Melanoma-in-situ  1 1.01 – 4a >4

0.5 1 2 2 vs 2 +

a Consider sentinel lymph node dissection before definitive excision in cases where Breslow depth exceeds 1 mm or when melanoma invades to Clark’s level IV.

Fig. 1. Mohs’ micrographic surgery. (A, B) A beveled specimen is obtained with a margin of normal-appearing tissue. (C, D) The tissue is divided, inked, and mapped before processing of frozen sections. Precise mapping allows for directed extirpation of remaining tumor. (Courtesy of Dr. Stuart Zweibel, Mt. Kisco, New York.)

J.A. Carucci / Dermatol Clin 20 (2002) 701–708

MMS is that the surgeon excises, maps, and reviews the specimen personally, minimizing the chance of error in tissue interpretation and orientation. MMS has gained acceptance as the treatment of choice for recurrent skin cancers and primary skin cancers located on anatomic sites requiring maximal tissue conservation for preservation of function and cosmesis [14 – 17]. The use of the technique depends on the ability of the Mohs’ surgeon to detect cancer on the frozen sections.

Detection of melanoma on frozen sections The use of MMS for melanoma depends on the surgeon’s ability to detect melanoma when interpreting frozen sections. Zitelli et al [18] studied 221 specimens from 59 patients and found they were able to detect melanoma on frozen sections with 100% sensitivity and 90% specificity. Frozen sections were compared with paraffin sections from each sample. In another study, Zitelli et al [19] reported their ability to achieve narrow margins and low recurrence rates in 95% of 535 consecutive patients with melanoma treated by MMS. They state that their overall low recurrence rate (0.5%) and ability to achieve narrow margin excision (6 mm) in 83% of patients support their ability to detect atypical melanocytes on frozen sections. The authors caution that both experience and an excellent frozen section laboratory are necessary to visualize melanomas accurately. Others caution against using frozen section in the diagnosis of melanoma because of decreased ability to detect melanocytes with adequate sensitivity. Nield et al [20] report significant differences in tumor thickness values for melanoma obtained by frozen and paraffin sections. In their study, thickness was either overestimated or underestimated on frozen sections. In another study, Shafir et al [21] found that in 29 consecutive cutaneous melanomas, thickness measured on frozen section was 0.1 to 0.4 mm greater than that measured on paraffin-embedded sections. They further caution that frozen section diagnosis of regressing melanoma is difficult and is accomplished best with paraffin-embedded specimens.

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3 mm are usually obtained. Frozen sections are processed and slides are examined by the Mohs’ surgeon. Remaining tumor is then removed in a directed fashion with margins of 3 mm in subsequent stages. Mohs’ surgery offers the advantage of examination of virtually 100% of the peripheral margin rather than sampling achieved by examination of conventional sections. MMS offers optimal patient convenience because tumors can be excised and repairs performed in a single day when the freshtissue technique is used. In contrast, MMS was originally performed by a fixed-tissue technique (chemosurgery) whereby tumors were fixed overnight with zinc chloride paste (Fig. 2). Initial tumor excision and excision of subsequent stages took place over the course of days. In these cases, wounds were managed by granulation or delayed reconstruction. Mohs [24] first reported the use of chemosurgery (fixed-tissue technique) for melanoma in 1950. In a study of 20 patients, he reported a 35% 5-year survival rate. He later reported a 50% 5-year survival rate in a larger cohort in 1956 [25]. In 1977, Mohs [26] reported three local recurrences in 103 cases treated using the fixed-tissue technique. In this report, more than 80% of melanomas treated by Mohs were Clark’s level IV and V. Zitelli et al [22] in 1989 reported on 200 cases of melanomas with an overall cure rate of 65%. Melanomas treated in this study also were advanced with almost one third level V. Snow et al [27] reviewed the treatment results of 179 cases from the Mohs’ melanoma registry. There were 61 cases treated by the fresh-tissue technique and 113 cases treated by a hybrid fixedtissue technique. Data were compared based on treatment technique versus tumor invasiveness and

MMS for melanoma Mohs micrographic surgery is gaining popularity as a treatment for melanoma [19,22,23]. For the first stage, the tumor with a margin of clinically uninvolved tissue is excised, inked, and mapped by the Mohs’ surgeon. For melanoma, initial margins of

Fig. 2. In the fixed-tissue technique, zinc chloride paste is applied overnight before Mohs’ excision. (Courtesy Dr. Stuart Zweibel, Mt. Kisco, New York.)

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5-year survival data were concordant regardless of treatment type. A landmark study of MMS, fresh-tissue technique, for the treatment of primary cutaneous melanoma was performed by Zitelli et al [19]. In this study, 535 patients with 553 primary melanomas were treated by fresh-tissue MMS. Metastatic rates and 5-year survival rates were equivalent to or better than historic controls treated by standard wide-margin surgery. Most tumors (83%) were excised with margins of 6 mm. Local recurrences caused by inadequate excision were rare (0.05%). The authors state that the ability to achieve excision with narrow margins with a low rate of local recurrence validates the ability to detect melanoma on frozen sections with adequate sensitivity and specificity.

Melanoma margins revisited In a related study by Zitelli et al [18], the margins of excision required to clear 553 melanomas cleared by MMS were determined. The authors found that margins of 6 mm were required in 83% of melanomas, 9-mm margins were required to remove 95% of melanomas, and 1.2-cm margins were required to remove 97% of melanomas. The authors concluded that predetermined margins of excision should include 1 cm of normal skin for melanomas on the trunk and proximal extremities less than 2 cm in diameter, or a 1.5-cm margin for lesions larger than 2 cm in diameter. They recommended margins of 1.5 cm for melanomas of the head, neck, hands, and feet less than 3 cm in diameter and a margin of 2.5 cm for lesions larger than 3 cm in diameter. Robinson [28], using Mohs’ surgery with both frozen and paraffin sections, showed that margins less than 6 mm removed only 23% of 16 LM and that margins up to 1.3 cm were required to remove all 16 tumors. Cohen et al [29] excised 45 LMs and lentigo maligna melanomas (LMM) by Mohs’ surgery and showed that margins of 6 to 10 mm were required to clear all tumors. In another study by Zalla et al [30], the average margin required for clearance was 8.3 mm for in situ melanoma and 11.1 mm for invasive melanoma. In contrast to Zitelli et al [19], only 50% of patients were clear with margins of 6 mm. Although 2.6 cm were required to clear 95% of all tumors, 50% of invasive tumors were cleared with margins of 6 mm. Accurate assessment of subclinical extension in these studies was based on the ability of the Mohs’ surgeon to assess the presence of melanoma cells on frozen sections. Attempts have been made to increase

the sensitivity of detection of melanoma by modifying the Mohs’ technique.

Modified Mohs’ surgery Special histologic stains Special histologic stains have been used in an effort to increase sensitivity and specificity of detection of malignant melanocytes at the margins of LM. Commonly used special stains have included S-100, Melan-A, HMB-45, and Mel-5 (Table 3). S-100, an acidic Ca2 + and Zn2 + binding protein found in the cytoplasm and nucleoplasm, may be involved in the regulation of diffusion of monovalent cations across membranes [31]. S-100 is sensitive for melanoma and is particularly useful in detection of spindle cell or desmoplastic melanoma [32]. Although sensitive for the dermal component of melanoma, S-100 may not be strongly positive in the epidermis. In addition to melanoma, S-100 stains benign melanocytic lesions, dendritic cells, histiocytes, Schwann cell, muscle, chondrocytes, and eccrine and apocrine cells [31,32].

Table 3 Special histologic stains used to enhance melanoma detection Histologic stain Antigen S-100

Mel-5

HMB-45

Melan-A

Positive staining 2+

Acidic Ca and Zn2 + binding protein

Desmoplastic melanoma Dendritic cells Muscle cells Histiocytes Schwann cells Chondrocytes gp75 (melanocyte Melanoma glycoprotein) Benign nevi Pigmented Bowen’s disease Pigmented actinic keratosis Lentigo Lichen planus – like keratosis 30 – 35 kd Melanoma melanosomeClear cell tumor associated Angiolipoma glycoprotein Lymphangiomyomatosis MART-1 (22-kd Melanoma cytoplasmic Clear cell tumor melanosome Angiolipoma associated Lymphangiomyomatosis glycoprotein)

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The Melan-A antigen is a 22-kd, cytoplasmic melanosome-associated melanocyte differentiation antigen and is present in 80% to 100% of melanomas [33,34]. Homogeneous staining was reported in up to 72% of tumors with Melan-A [33]. Zalla et al [30] found that Melan-A was the most consistently crisp stain when compared with S-100, Mel-5, and HMB-45 in the treatment of melanoma. HMB-45 is a mouse monoclonal antibody that recognizes a 30- to 35-kd, melanosome-associated sialated glycoprotein [35,36] that is localized to stage II and III melanosomes in neoplastic melanocytes. Although HMB-45 has been reported to be up to 97% sensitive for melanoma on paraffin sections, it is often negative on spindle cell, desmoplastic, or neurotropic melanomas [32]. Mel-5 recognizes gp75, an abundant glycoprotein in melanocytes [37]. Although staining for melanoma has been reported to be brisk, Mel-5 stains nonmelanocytic lesions including lichen planus – like keratoses, pigmented actinic keratoses, and pigmented Bowen’s disease. Gross et al [38] report successful treatment of two patients with LM using a rapid (75-minute) Mel-5 staining technique. Both patients remained tumor free at 15 and 18 months. In that study, the authors used a negative control from contralateral skin and a positive control from the center of the LM. Zalla et al [30] report successful treatment of melanoma using Melan-A, HMB-45, Mel-5, and S-100. In that study, 68 patients were treated including 46 with melanoma in situ and 22 with invasive melanoma. In their study, Melan-A was reported to be the most consistently crisp and easily interpretable immunostain. Menaker et al [39] recently described a rapid HMB-45 technique for in situ and invasive melanoma. In their study of 20 patients, HMB-45 was 100% sensitive and 95% specific for detecting melanoma when compared with horizontally sectioned paraffin-embedded specimens.

Rush paraffin sections Permanent sections have been used to aid recognition of malignant melanocytes in LM and LMM. Cohen [40] reports successful treatment in 45 patients with LM and LMM over a mean follow-up period of 29.2 months. In a follow-up study, Cohen et al [41] reported 1 recurrence in 45 patients over a follow-up period of 50 months for an overall cure rate of 97%. As with other types of staged procedures, extirpation and repair take place over several days.

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Special situations Lentigo maligna Lentigo maligna is an indolent form of melanoma in situ that occurs predominantly on sun-exposed areas of the head and neck in elderly individuals [7]. There has been controversy as to whether LM represents a precancerous lesion rather than a skin cancer; however, the threat of progression to invasive LMM exists [42]. Because studies have shown that prognosis of LMM is dependent on depth of invasion as with other subtypes of invasive melanoma, detection and treatment of LM before progression to invasive disease are necessary [43]. Surgical excision with clear margins is the treatment of choice for LM [7]. Both conventional and MMS excision have been used successfully in the treatment of LM. Cohen et al [40] reported high cure rates for LM using MMS with rush paraffin sections. Gross et al [38] reported successful treatment of LM using MEL-5 immunostain to increase sensitivity. Stonecipher et al [44] used rush paraffin sections stained with HMB-45 for treatment of two cases of LM and three cases of LMM. Melanoma of the hands and feet Melanoma involving the nail unit tends to have poorer prognosis with 5-year survival rates for stage I and II disease ranging between 38% and 61% [45 – 47]. This is likely caused by delays in diagnosis and adequate treatment. Tseng et al [48] reported 48 patients with acral lentiginous melanoma (ALM) in which 71% had a depth of 1.5 mm or greater. Metastases were present in 56%. The authors recommended excision to bone followed by grafting for lesions less than 1 mm in depth and amputation of the distal phalanx and sentinel lymph node biopsy for lesions greater than 1 mm in depth. Fourteen patients with nail apparatus melanoma were treated with MMS by Brodland [49]. After a mean follow-up period of 7.7 years 6 patients were alive and disease free, 3 were alive and disease free after local recurrence, 2 had died disease free of other causes, 2 died from widespread disease, and 1 was disease free after lymph node dissection and interferon-alfa for regional disease. The author proposed that risk of local recurrence with little effect on survival was acceptable when compared with disability secondary to amputation. Banfield et al [50] report treatment of nail apparatus melanoma by MMS using paraffin sections stained with hematoxylin and eosin, Schmorl’s, and ammoniacal silver nitrate and

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immunostaining with HMB-45 and S-100. Their patient was tumor free at 1 year. Melanoma involving the foot can be a therapeutic challenge. Griego and Zitelli [51] report successful treatment of recurrent acral melanoma using HMB-45 immunostaining. In their report, the melanoma recurred 6 years after standard excision with 9 of 12 specimens positive for tumor. The recurrent tumor failed MMS and the fourth recurrence was treated with the modified technique using HMB-45. In that case the authors found that HMB-45 was positive in areas known to be positive by frozen and paraffin sections and in nearby areas where permanent sections were equivocal or negative. Their patient remained tumor free at 22 months. Melanoma of the oral cavity Melanoma of the oral cavity, although rare (0.2% of all melanomas), can be devastating with 5-year survival rates ranging from 20% to 35% [52]. Oriba et al [53] report treatment of advanced melanoma using the fixed-issue technique. Their patient was a 77-year-old man with a 6-cm nodular melanoma of the lip and buccal mucosa that extended to a depth of 4 mm and Clark’s level V. In addition regional metastases were discovered at presentation. After a neck dissection was performed, fixed-tissue Mohs’ surgery was performed to debulk the primary tumor. The primary tumor was cleared, the wound healed secondarily, and the patient was subsequently treated with local radiation. The patient eventually died of systemic metastatic disease; however, the tumor did not recur locally. The authors proposed that tissuesparing chemosurgery allowed for increased quality of life as compared with radical surgery that would have otherwise been performed. Melanoma of the nose Melanoma on the nose was reported to have an incidence of 0.4% with desmoplastic melanoma being the predominant subtype [54]. Excision to cartilage followed by flap or graft repair has been recommended [3]. Mohs et al [55] reported a series of 10 patients with melanoma of the nose treated by MMS, fixedtissue technique. There were three patients who developed widespread metastatic disease over 5 to 7 years, although no local recurrences were recorded. Two of these three cases were nodular melanoma, Clark’s level V, and the other was an amelanotic, desmoplastic LMM, Clark’s level V. The authors reported a 62.5% 5-year survival rate for eight deter-

minate cases. Follow-up ranged from 5 to 10 years for successfully treated patients. Melanoma of the ear Melanoma of the ear occurs most frequently on the helix [3]. Cole et al [56] report successful treatment by excision of skin with cartilage sparing followed by graft repair. Others advocate wedge excision for melanomas thicker than 1 mm [3]. Mohs [57] reported a series of 17 patients with auricular melanoma treated by MMS, fixed-tissue technique. Four patients developed distant metastatic disease. Twelve (75%) of 16 patients were disease free at 5 years. Of the 12 successfully treated, 5 patients had melanomas invasive to Clark’s level IV or V. Periorbital melanoma Periorbital melanoma accounts for up to 7% of head and neck melanomas [58]. Because of the thinness of the skin and high likelihood of subdermal invasion, wedge excision of lesions on the lash margin has been suggested with narrower margins reserved for lesions involving eyelid skin [58]. Mohs [59] used both the fixed- and fresh-tissue technique in the treatment of periorbital melanoma. The fixed-tissue technique was used when there was no involvement of the lid margins or bulbar conjunctiva. A modified fresh-tissue technique was used when these structures were invaded. Mohs reported on five cases of periorbital melanoma, three of which were invasive to Clark’s level III. There were no recurrences in four of five cases over a follow-up period ranging from 4 to 36 years. In one case, there were both local and regional metastases over 2 years.

Summary Surgical excision with clear margins remains the treatment of choice for melanoma. Under appropriate conditions MMS may offer a means of achieving clear margins while sparing normal tissue. This requires a Mohs’ surgeon expert in interpretation of melanocytic lesions and excellent technical support. As the popularity of special histologic stains continues to grow these may offer and additional means to increase sensitivity and specificity in the detection of melanoma.

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