C.C. Huang, MD
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
ABSTRACT
Lentigo maligna (LM) is a pigmented lesion that occurs most commonly on the sun-exposed skin of the head and neck of an older patient. LM can be difficult to completely remove due to its occasional extensive subclinical extension. Surgical treatments, including standard excision and margin-controlled excision (Mohs micrographic surgery or rush permanent sections), are reviewed. Immunostains that can increase sensitivity and specificity of margin-controlled excision are discussed, and other nonscalpel treatments including destruction, topical imiquimod, radiation therapy and cryotherapy are briefly discussed. The gold standard treatment for LM is margin-controlled excision.
Key Words: lentigo maligna, lesion, margin-controlled excision
Clinical Features
Lentigo maligna (LM) is a pigmented lesion that occurs most commonly on the sun-exposed skin of the head and neck of an older, fair-skinned patient. LM can display heterogeneous pigmentation with areas of brown, black, pink, and white (signifying regression). LM frequently has ill-defined borders and microscopic extension that can make determination of the clinical borders and complete removal of the lesion difficult.1
Histology
Typically, atypical solitary or nested melanocytes can be seen along the basal layer or extending periadnexally. Multinucleated melanocytes can be seen.2 Consistent with LM appearing most commonly in the elderly, elastosis, epidermal atrophy, and effacement of rete ridges are common associated findings.1
Atypical melanocytes in LM can extend significantly beyond what appear, to the naked eye, to be the clinical margins of the lesion. This phenomenon has been well-documented in the literature where complete removal of a relatively small LM results in the creation of a surprisingly large wound.3-5 While the significance of these solitary and/or focal extensions of atypical melanocytes is unknown, the current standard of treatment is to excise them completely.
Risk of malignant transformation
It is believed that an LM will slowly increase in surface area until it invades the dermis and becomes lentigo maligna melanoma (LMM). There are numerous case reports that document this and argue against observation of LM and for its prompt surgical excision.6-9 To date, there are no longitudinal, prospective studies that measure the incidence of this malignant transformation. Therefore, we are left with expert opinion estimates which place this risk at 33%-50%.10-12 To date, one study has used epidemiologic analysis in an attempt to quantify the annual and lifetime risk of malignant transformation.13 This study used three comprehensive data sources that were representative of the Caucasian population of the United States. The authors deduced that for a 45-year-old Caucasian with LM, the risk of malignant transformation by age 75 was 3.3% with a lifetime risk of 4.7%. For a 65-year-old Caucasian patient with LM, the corresponding risks were 1.2% and 2.2%. The authors acknowledged limitations to their study, including the fact that data was retrospective and not gathered expressly for the purpose of determining the incidence of malignant transformation of LM. Nevertheless, theincidence determined from this study is the closest thing to evidence-based data that currently exists.
Biopsy Technique
Whenever possible the entire suspected lesion, or as much of the suspected lesion as possible should be biopsied. Deep shave biopsy, excisional, or multiple incisional biopsies (e.g., multiple shaves or punch biopsies) are acceptable techniques. Submitting as much of the lesion as possible will give the most complete histologic microstaging information and allow for the most appropriate initial therapy.14 Note that two studies have shown that suspected LM, when biopsied, can have a central invasive component 16%-32% of the time.21-22 Also note that incisional biopsies from a lesion that is diagnosed as a melanoma have not been shown to decrease survival.15-18
Treatment
Surgical
Surgical excision is the current most definitive treatment for LM. The most widely utilized excisional techniques are standardexcision, “slow Mohs” (staged, margin-controlled excision with rush permanent sections), and Mohs micrographic surgery (staged, margin-controlled excision with frozen sections).
Per the 1992 National Institutes of Health Consensus Conference, recommended margins for standard excision are 0.5cm.19 This margin is often inadequate due to the subclinical extension that can occur with LM.6-9 Note in Tables 1 and 2 that the average margin required in clear LM in 90%-95% of cases is significantly greater than 0.5cm. One should take care to avoid having to perform a re-excision due to positive margins since reexcision is wasteful of normal surrounding tissue, results in rewounding of the patient, exposes the patient to the risks of surgery a 2nd time, requires more physician and patient time, and increases medical costs. Thus, excisional techniques that yield the highest tumor removal rate while at the same time preserving maximal normal tissue are favored by those who deal with LM frequently. Two techniques in particular are “slow Mohs” and Mohs micrographic surgery (MMS).
“Slow Mohs” is the staged excision of peripheral and deep margins with rush permanent sections, followed by repair of the resulting wound. Several variants have been described such as the “square” procedure and the “polygonal method”.20-22 They all accomplish the common goal of verifying clear peripheral and deep margins before wound repair to minimize the risk of persistent or residual disease while simultaneously sparing normal tissue. Initially, circumferential, full-thickness skin strips 2mm in width are harvested 0.5cm from the LM. This 0.5cm margin is measured under both bright surgical lighting and Wood’s lighting. The outside circumferential margin of the strips is marked with permanent ink, and the pathology lab is instructed to section the strips tangentially along this inked margin. Strips are divided so that they are approximately 2.5cm long and will fit inside a standard paraffin embedding cassette. Various mapping methods to document the location of the harvested skin strips such as marking suture, permanent marking ink, or incisional nicks in the skin are used. The resulting trough-like wound is closed with a running or interrupted cutaneous suture until pathology results are available. The central tumor is left intact until all peripheral margins are cleared. Reexcision of additional skin strips is done with a 0.5cm margin ONLY from areas of positivity. This spares excision of normal tissue. Strips are harvested and the resulting trough-like wounds closed until all peripheral margins are clear. Then, all tissue within the incised skin strips is excised and submitted for deep margins. Since LM is an epidermal lesion, deep margins are generally clear. However, two studies to date have documented significant incidence of invasive tumor upon breadloafing of the central tumor (Table 1).21,22 For this reason, some advocate excising the central tumor with the initial harvesting of skin strips in order to better guide treatment.21,22 If there is an invasive component noted, further appropriate treatment should be done as indicated by the pathology report. The discussion of treatment of invasive melanoma is beyond the scope of this article, and the reader is directed to other comprehensive reviews.23 Using this method, 5-year cure rates approaching 100% have been reported.1,21,22 (See Table 1).
| Year | Author | # of lesions | Follow up | Recurrence | Margin Required | Notes |
| 2002 | Agarwal-Antal, et al21 | 92 LM | Up to 4 yrs | 0 | • 42% clear with 0.5cm | • Central tumor positive for invasive tumor 16%. |
| 1998 | Hill, et al22 | 38 LM, 28 LMM | Average 25 mos (range 10-48 mos) | 1 | • 62% clear with 0.5cm | • 32% were invasive melanoma. 43% of these (14% of the 66 original cases) were diagnosed as invasive melanoma only after breadloafing of the central tumor. 2 required more than 1 layer in 50%. LMs <300mm2 required more than 1 layer in 26%. |
Table 1: Summary of studies of “Slow Mohs” for LM
MMS theoretically accomplishes the same result in less time since frozen section results are available within the hour instead of the 24 hours that rush permanent sections require. With MMS, the initial tissue layer encompassing the entire tumor is taken with a 2- 3mm margin. The deep and peripheral margins of the layer are examined and any residual tumor is precisely excised with the aid of a tissue map. This process is repeated until margins are clear. Some Mohs surgeons then send an additional tissue layer or melt and send the final clear layer from MMS for permanent sections and wait for those margins to be called clear before repairing the wound. Others close the wound immediately without sending additional tissue. Using this method, 5-year cure rates approaching 100% have also been reported.1,24,25 (See Table 2)
| Year | Author | # of lesions | Follow up | Recurrence | Margin Required | Notes |
| 1995 | Cohen1 | 26 LM, 19 LMM | Average 58 months | 1 | ||
| 1998 | Robinson24 | 16 LM | 5 yrs | 1 | • 19% clear with 0.3cm | • Central tumor positive for invasive tumor 0%. |
Table 2: Summary of studies of Mohs micrographic surgery for LM
While “slow Mohs” has gained practically universal acceptance as an effective way to completely remove LM while sparing maximal normal tissue, MMS has not been as widely accepted due to several technical limitations that lie mainly in difficulties of processing and interpreting frozen sections of atypical melanocytes. Freeze artifact can cause normal keratinocytes to become vacuolated and to resemble melanocytes. Inflammatory cells, epidermal spongiosis, or coincident actinic keratosis may obscure melanocytes. Tissue may become folded or compressed at the epidermis during its transfer from the cold environment of the cryostat to a warm slide. Other confounding artifacts are tissue chatter, tangential sectioning of the epidermis, and bubbles. Ultimately, the Mohs surgeon may be faced with distinguishing between malignant scattered melanocytes and scattered atypical melanocytes seen in sun damaged skin. This is a challenging task even for a dermatopathologist.26-31
In a recent study specifically concerning this challenge, five pathologists graded 301 slides taken from 27 patients who had “slow Mohs” for LM.26 Concordance between pathologists was measured by the K statistic where a negative value indicates less agreement than would occur by chance, a 0 value would indicate exactly the amount of agreement indicated by chance, and positive value would indicate more agreement than would occur by chance. A value of 1 indicates perfect agreement. The study was divided into three phases. In phase 1, all slides were randomized and diagnosed as positive or negative. Agreement was moderate with K=0.4-0.5. In phase 2, every 3rd slide was read as positive or negative. Agreement was good with K=0.6-0.9. In phase 3, slides were organized into cases allowing evaluation of the slides with the benefit of positive control (central tumor) and negative control (when available). Agreement was moderate with K=0.4-0.5. Slides from this study were processed as rush permanent sections in the setting of “slow Mohs.” One would expect for interpretation, reproducibility, and agreement to be less in the setting of the frozen sections used with MMS.
To make this task easier, some Mohs surgeons use immunostains including HMB-45, Mel-5, MART-1, and S-100 (see Table 3).32-36 No stain can reliably differentiate between melanoma cells and benign melanocytes; however, one that reliably stains all melanocytes and the epidermal component of melanoma allows for diagnosis based on pattern recognition. While immunostains can improve the sensitivity and specificity of Mohs frozen sections, they do increase tissue processing time to 60-90 minutes per layer and are relatively costly, adding roughly $50 US to each layer of tissue processed. At the present time, the majority of cases of “slow Mohs” and MMS for LM do not use immunostains.
| Year | Author | # of lesions | Immunostain | Antigen | Notes |
2002 | Kelley, et al35 | 7 LM | MART-1 (Melanoma Antigen Recognized by T-cells | MART-1, transmembrane protein expressed on benign and malignant melanocytes | • 100% correlation between MART-1 frozen sections paraffin embedded sections. The same tissue was used for both. |
1999 | Menaker, et al34 | 18 MMis | HMB-45 | HMB-45, cytoplasmic antigen partially composed of sialic acid and localized to immature melanosomes. | • 11/20 stained positive on the 1st layer of Mohs surgery. There was 100% correlation between HMB-45 frozen sections paraffin embedded sections. The same tissue was used for both. |
1998 | Gross, et al33 | 2 LM | Mel-5, a murine IgG antibody | TRP-1, tyrosine-related protein. | • Both cases were clear with the 1st tissue layer, but there was 100% correlation between frozen section positive and negative controls and H&E stains. |
1993 | Stonecipher, et al36 | 3 LM, 2MM | HMB-45 | See above | • 5 case reports demonstrating the utility of HMB-45 (1 case) and supplemental vertical sections (3 cases). |
Table 3: Summary of studies of the use of immunostains with Mohs micrographic surgery for LM
Destructive
Electrodessication and curettage and laser ablation
Destructive methods of treatment such as electrodessication and curettage and laser are rarely used to treat LM due to several major disadvantages.37-38 These methods are usually relatively superficial and do not adequately treat deeper periadnexal melanocytes. At some point after treatment, these melanocytes can migrate back to the epidermal surface and result in recurrence.
Lastly, there is no pathology generated from a destructive method, and, therefore, margins cannot be assessed.
Cryotherapy
While there are reports documenting the efficacy of cryotherapy, this type of treatment is generally only considered if the patient does not wish to have or cannot have surgical excision.39-42
Radiation therapy
Radiation therapy is not a first line therapy and probably has its best use as an adjuvant therapy in high-risk disease or for metastatic LMM.43-45
Medical
Imiquimod
There are case reports documenting the effectiveness of imiquimod cream in the treatment of LM. This is a developing treatment modality that may have utility in the future. At present, further adequately powered controlled trials with appropriate follow up are needed to establish efficacy.46-49
Conclusion
- Lentigo maligna (LM) is a pigmented lesion that occurs most commonly on the sun-exposed skin of the head and neck of an older, fair-skinned patient.
- LM is at risk to undergo malignant transformation. The best estimate of malignant transformation is that a 45-year-old Caucasian will have a 3.3% chance by age 75 and a lifetime risk of 4.7%. The corresponding percentages for a 65-year-old Caucasian are 1.2% and 2.2%.
- When biopsying a suspected LM, as much of the lesion as possible should be biopsied to give the most accurate histologic microstaging information. A significant number of suspected LM will also have an invasive component.
- Excision is most often the treatment of choice. Guidelines from the 1992 NIH Consensus Conference recommend an excisional margin of 0.5cm. By using “slow Mohs” and Mohs micrographic surgery (MMS), one can potentially obtain more specific tumor removal while maximally sparing normal tissue. MMS is probably the less favored of the two techniques due to technical difficulties in the frozen section preparation. Various immunostains have been used to help increase the sensitivity and specificity of MMS frozen sections. Five-year cure rates can approach 100% with these two specialized techniques.
- Destructive techniques such as electrodessication and curettage and laser ablation are not favored, since they are superficial in effect and can result in incomplete tumor removal and recurrence. Cryotherapy and radiation therapy are generally considered for nonsurgical candidates.
