Lentigo maligna (LM) is a variant of melanoma in situ that mainly affects chronically sun-exposed parts of the body in older patients.1 This type accounts for between 79% and 83% of all cases of melanoma in situ2 and can run a very slow course (up to decades) before progressing to its invasive form, lentigo maligna melanoma (LMM). Four to 15% of all melanomas are LMs or LMMs,3 and most affect the head and neck (86% of all cases).4 The incidence of LM is rising, and while most cases are described in patients aged between 65 and 80 years, there have been reports of LM in patients aged 20 to 30 years; in some large series 10% of the patients were younger than 40 years.1,5

No specific protocols have been published for the treatment of LM, and because of its special features, its management is still debated. LM generally occurs in elderly patients, affects parts of the body that have been damaged by the sun or carry a risk of cosmetic or functional defects, has poorly defined clinical and histologic margins, and recurs frequently following treatment.6 We review the diagnosis of LM, including methods and criteria, and provide an overview of the different treatment modalities available, with a description of the advantages and disadvantages of each in order to guide clinical decision making.

We performed a literature search using the Cochrane and MEDLINE databases.

The search terms entered in PubMed were Hutchinson melanotic freckle, lentigo maligna, diagnosis, therapy, surgery, and radiotherapy. Preference was given to reviews and articles published in English or Spanish. We also reviewed the main clinical management guidelines for melanoma.

LM presents clinically as a slow-growing, asymmetric macule with irregular, poorly defined borders and varied pigmentation (dark gray, light brown, dark brown, black, and white [areas of regression]).3,7 Albeit rarely, primary or recurrent LM can present clinically and histologically as an amelanotic lesion.8,9

Histology remains the diagnostic method of choice in LM.10 Characteristic histologic findings are the proliferation of atypical melanocytes along the dermal-epidermal junction; cells are often oriented perpendicular to the surface, and involvement of the periadnexal structures of the epithelium is a common finding. In more advanced lesions, nests of cells at the dermal-epidermal junction and multinucleated giant cells may be observed. Occasionally, there may be pagetoid spread, epidermal atrophy, and solar elastosis in the dermis. The papillary dermis may contain melanophages and a chronic inflammatory infiltrate.8

It is sometimes difficult to distinguish atypical melanocytes from the atypical junctional melanocytic hyperplasia seen in actinically damaged skin. A useful approach is to take a control biopsy from the contralateral side of the face.11

In general, biopsy of suspicious or changing pigmented lesions on the face is recommended.12 Excisional biopsy is the most accurate diagnostic method in LM, but because lesions are often large and located in cosmetically sensitive areas, punch biopsy is the most widely used procedure,13 despite the problem of sampling error.14 Based on observational studies by Stevens and Cocherell,15 deep incisional biopsy extending as far as the subcutaneous tissue with a punch of at least 5mm can minimize this source of error. For large lesions, mapping and taking multiple punch biopsies of the most representative sites (darker or palpable areas suspicious for invasion) offers a possible approach. The use of complementary techniques such as dermoscopy and confocal reflectance microscopy (CRM) is also useful.

Some facial lesions that are clinically insignificant, i.e., that do not meet the ABCD criteria (Asymmetry; Borders, uneven; Color, multiple; Diameter, >6mm), are histologically malignant.16,17 Routine dermoscopy is therefore a useful complementary tool that can help to identify such lesions early so that even lesions that appear clinically benign can be excised. Schiffner and Stoltz18 reported that dermoscopy has a sensitivity of 89% and a specificity of 96% for the early diagnosis of LM when several dermoscopic features are detected and that the presence of a single feature is not diagnostically useful.

The most characteristic dermoscopic finding in facial LM lesions is a pigmented pseudonetwork, which is an area of homogeneous pigmentation disrupted by follicular or adnexal openings on the face.19

Other dermoscopic criteria for LM/LMM are asymmetric pigmented follicular openings (corresponding to follicular invasion by tumor melanocytes); dark rhomboidal structures (proliferation of melanocytes around the interfollicular spaces); slate-gray dots and globules (melanin-laden macrophages in the superficial dermis that may form granular, ring-like images in several areas); dark streaks (rows of melanoma cells in the epidermis or superficial dermis); homogeneous areas (complete obliteration of follicular openings by invading melanoma cells); and isobar structures (concentric pigmented circles around the follicular openings).

Another recently described pattern is a series of brown or blue-gray dots in lines that form a zigzag.20

Dermoscopy is also useful for selecting biopsy sites, distinguishing LM from other pigmented lesions on the face,18,19 delineating surgical margins, and assessing and monitoring treatment response.

Early Diagnosis: The Schiffner Dermoscopic Progression Model

Rapid recognition of the first dermoscopic signs of primary or recurrent LM is important during follow-up. Schiffner and colleagues18,21 designed a progression model for LM that shows the characteristic dermoscopic structures of LM lesions from the earliest to the latest phases in the following order: dots around the hair follicle, short streaks, rhomboidal structures, follicular openings, and homogeneous areas-obliteration of follicular openings (Figs. 1 and 2).

Figure 1.

A, Lentigo maligna. Macule with irregular light and dark brown pigmentation. B, Dermoscopic image of the same lesion showing dermoscopic features of early-phase lentigo maligna: follicular openings with asymmetric pigmentation and rhomboidal structures.

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Figure 2.

A, Dermoscopic image of early-phase lentigo maligna showing irregularly distributed slate-gray dots and globules (red arrows), short dark streaks, early rhomboidal structures (black arrow), and asymmetric perifollicular pigmentation (asterisks). B, Dermoscopic image of lentigo maligna showing follicular openings with asymmetric pigmentation, some of which have signs of early obliteration (red arrows). C, Image showing isobar structures (asterisk), rhomboidal structures (red arrow), and follicular openings with asymmetric pigmentation. D, Image of histologically confirmed lentigo maligna melanoma following biopsy taken of area marked by the asterisk, showing homogeneous areas with obliterated follicular openings.

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Differential Diagnosis of Pigmented Facial Lesions

It can be difficult to distinguish LM from other pigmented lesions (solar lentigines, pigmented actinic keratosis, seborrheic keratosis, benign lichenoid keratosis) by simple visual examination.

Furthermore, dermoscopy alone may not be sufficient as LM shares several dermoscopic features with other lesions.22,23

The most useful noninvasive diagnostic approach is the correlation of dermoscopic and clinical findings. Table 1 summarizes several key dermoscopic features for distinguishing between pigmented lesions on the face.

Table 1.

Differential Diagnosis of Pigmented Facial Lesions by Dermoscopy.

	Lentigo Maligna	Pigmented Actinic Keratosis	Solar Lentigines/Seborrheic Keratosis	Benign Lichenoid Keratosis
Pseudonetwork	+	+	+	+
Homogeneous areas	+	−	−	−
Rhomboidal structures	+	+	−	+/−
Annular granular pattern	+	+	−	+
Grayish-brown granules	Irregular distribution and size	Similar color, size, and distribution (predominantly perifollicular)	−	Diffuse or localized distribution
Asymmetric perifollicular pigmentation	+	+/−	−	-
Moth-eaten border	−	+/−	+	−
Fingerprint-like structures	−	−	+	−

LM and pigmented actinic keratosis are known to be clinically similar, but there are cases in which histologic distinction can be difficult. In such cases, immunohistochemical staining with human melanoma black 45 and Melan-A may be useful; these markers can be combined with Giemsa staining, whereby melanin deposits acquire a greenish color, allowing melanocytes to be distinguished from melanophages.

Almost all of the dermoscopic features of LM are also found in pigmented actinic keratosis, with the exception of homogeneous areas, which are highly specific for LM/LMM.10

In summary, the most specific dermoscopic structures seen in pigmented actinic keratosis are multiple brown-grayish dots and globules with a similar size and color and a perifollicular arrangement (more regular than in LM), rhomboidal structures, and an annular granular pattern. These first 3 structures are the most common (Fig. 3). Other patterns are a brown to gray pseudonetwork, a superficial fragmented pseudonetwork, and follicular openings with yellowish keratotic material surrounded by a whitish halo giving a target-like appearance.10,24

Figure 3.

A, Dermoscopic image of lentigo maligna (rhomboidal structures asymmetric perifollicular pigmentation, and granular pattern with asymmetrically distributed irregular globules). B, Dermoscopic image of pigmented actinic keratosis (multiple similarly shaped and colored brown-gray dots with a predominantly perifollicular distribution, and rhomboidal structures). C, Histologic image (hematoxylin-eosin, original magnification ×100) of the lesion in Figure 3A, showing proliferation of atypical melanocytes along the dermal-epidermal junction with involvement of the perifollicular epithelium. Melanophages and solar elastosis can also be observed in the dermis. D, Histologic image (hematoxylin-eosin original magnification ×100) of the lesion in Figure 3B, showing atypical pigmented keratinocytes at the dermal-epidermal junction and solar elastosis in the dermis.

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The exact percentage of cases of LM that progress to LMM is unknown, but based on studies published to date, progression rates would appear to be highly variable, ranging from 5% to 50%.3,33,34

No clinical, histologic, or biologic predictors of malignant transformation have been identified. An invasive component has been histologically demonstrated in 22% of fully excised LMs following diagnosis by incisional biopsy.2,7 The risk of LMM may be proportional to lesion size, as foci of invasive melanoma are seen more frequently in large lesions. The period of latency between the development of LM and progression to LMM can be long (10-50 years), but rapid progression (6 months) has also been reported. LMM should be managed like other invasive melanomas since prognosis for all these tumors is similar.35–38 Recurrence rates vary from 3% to 50%, depending on treatment. Rates of 3% have been associated with microscopically controlled excision, while rates of 50% (and even 100%) have been seen in LMs managed nonsurgically. Most recurrences present as in situ lesions,3 but invasive forms, which have a poorer prognosis due to the risk of metastasis, have been described.1,39,40

There is a notorious lack of prospective, randomized studies and specific guidelines and protocols on the management of LM. Nevertheless, the main guidelines on the management of melanoma11,12,41,42 address LM and should be consulted. The aim of treatment is to achieve cure and thereby prevent progression to invasive melanoma (LMM), which carries a risk of regional and distant metastasis.1 Treatment should be effective and initiated as early as possible; the treatment of choice is surgical excision whenever possible, especially in younger patients.5 The following factors should be taken into account when deciding on the best treatment modality: the patient's age and general state of health, comorbidity, life expectancy, size of lesion, location in cosmetically or functionally sensitive areas, accessibility and convenience of treatment, and patient preferences.43 Both patients and their relatives should be informed about the advantages and disadvantages of each treatment option. The levels of evidence and grades of recommendation associated with the different treatment options are shown in Table 2. (See Appendices A and B for the meaning of these classifications.)

Surgery is the mainstay of treatment, with a safety margin depending on Breslow thickness. A margin of 0.5cm is recommended for melanoma in situ and LM, but in certain cases this may be insufficient to remove all affected tissue and might lead to recurrence. Zalla et al.44 reported on a series of 46 LMs in which margins of 6mm achieved full excision in only 50% of cases. In another study of 92 LMs, 58% of lesions required safety margins of over 5mm to achieve complete clearance.45 These data confirm that the margins recommended by the National Institutes of Health for the treatment of LM46 may be insufficient.

The best surgical procedure for the treatment of LM and LMM in terms of ensuring complete excision involves the 3-dimensional study of the excised tumor before any type of reconstruction using Mohs micrographic surgery or microscopically controlled surgery with frozen or paraffin-embedded sections. One group of authors reported a 97% cure rate with the frozen-section technique in patients with LM and LMM.47 Mohs micrographic surgery was introduced in 1941 by Frederic Edward Mohs,48,49 although the technique and name have changed over the years. In all the variations, the entire excised tumor is histologically examined using horizontal and vertical sections or a section that includes the peripheral and deep margins after the tissue is flattened with a cryostat. Variations of histographic surgery that do not involve the flattening of peripheral margins but rather study peripheral and deep margins separately using vertical and horizontal sections are perfectly applicable in LM and are technically less complex than the conventional Mohs procedure.

Following a review of the literature on the treatment of LM and LMM, McLeod et al.50 showed that recurrence rates were lower after Mohs micrographic surgery and its variations than after conventional surgical excision with safety margins. This finding is consistent with what we have discussed here because the radial growth of atypical melanocytes may not be uniform, meaning that subclinical disease may exist beyond one of the resection margins, even in the case of wide excision. LM and LMM are mainly located on the face, and therefore better cosmetic and functional outcomes are achieved when the operator uses healthy tissue–sparing approaches, which are not incompatible with oncologic control. This principle is particularly relevant in recurrent LM, where lesions are less well defined and the chances of treatment success are lower.

Staged excision is a simple, acceptable alternative for treating LM and LMM and offers comparable results to those seen in Mohs micrographic surgery (Tables 3 and 4, Fig. 5). One recent study found that staged excision was associated with a significantly lower recurrence rate than Mohs, and there were no differences in the final size of the surgical defect.51 This technique, which was first referred to as the square procedure, consists of enclosing the target lesion and safety margins within a geometric figure (in this case a square) and histologically examining the peripheral margins using paraffin-embedded sections.52,53

Figure 5.

Sixty-five-year-old man with lentigo maligna. A, The lesion on the nasal dorsum. B, Under Wood's light the margins are more clearly defined. Note the ulcer on the bridge of the nose, caused by the use of continuous positive airway pressure. C, Inking of margins guided by Wood's light examination after biopsy confirmation of the diagnosis. D, Surgical defect after 2 steps of Mohs micrographic surgery using paraffin-embedded sections; all margins were positive. E, Final defect with clear margins after 3 steps.

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More recent alternatives are the perimeter technique54 and the spaghetti technique,68 which involve the same basic principle—evaluation of all peripheral margins before reconstruction—but differ from the previously described excision methodologies.

The main obstacle to the successful treatment of LM is the difficulty of distinguishing between atypical or dysplastic melanocytes and normal melanocytes in chronically sun exposed parts of the body. Failure to make this distinction can complicate diagnosis and lead to slow tumor recurrence.69 Paraffin-embedded sections are preferable to frozen sections, in which it is difficult to identify dysplastic melanocytes. In some cases, immunohistochemical staining may be needed to reach a definitive diagnosis. Nonetheless, several recent articles describing the use of immunohistochemical stains on Mohs frozen sections have reported rapid staining protocols (19 and 20 minutes for MART-1 and 35 minutes for MITF) that give results similar to those seen in paraffin-embedded sections.60,70–72 These results, however, need to be confirmed in larger series or controlled studies.

Because LM frequently affects older patients with comorbidities and involves large lesions requiring wide excision margins in cosmetically or functionally sensitive areas, nonsurgical treatments are sometimes required. These treatments are also necessary for patients who decline to undergo surgery. While the main advantages of nonsurgical treatments are good cosmetic results and low morbidity, these modalities are unfortunately associated with higher recurrence rates. In a study of melanoma in situ, Zalaudek et al.73 reported a mean (SD) 5-year recurrence of 6.8% (1.3%) for surgical excision and of 11.3%±8.5% for nonsurgical alternatives as a whole. The authors concluded that radiation therapy, which has similar recurrence rates to surgery, was the best alternative.73 Based on a survey conducted among British dermatologists in 2001, the most common nonsurgical treatments were cryotherapy and radiation therapy.74 The general limitations of nonsurgical treatments are summarized below.

• 1.

  Recurrence rates are higher because the whole tumor is not evaluated histologically and so invasive areas may be missed (sampling error).2 It is also difficult to treat deep periadnexal melanocytes, which explains why any treatment must reach a depth of at least 3 to 5mm, regardless of treatment modality.

• 2.

  Residual hypopigmentation following certain treatments may lead to delayed detection of recurrence during follow-up.

• 3.

  The efficacy of nonsurgical treatments has not yet been well established due to the lack of randomized controlled studies.

Regardless of the treatment modality employed, long-term follow-up is essential. In the following sections, we review the main nonsurgical treatments used in LM.

Imiquimod, a synthetic imidazoquinoline amine, is a topical immune response modifier that exerts its effect through the stimulation of both innate and acquired immunity. It has also been shown to induce apoptosis99 and exert antiangiogenic effects.100

After the first reported case of imiquimod-treated LM was published in 2000,101 by 2006 there were descriptions of 68 cases treated in this way according to a review of 15 reports in the English-language literaure.102 The authors of the review concluded that, because of the risk of leaving invasive or residual disease, “without controlled evidence and prolonged follow up, the use of imiquimod for LM must still be considered experimental.”102 The literature now contains reports of the use of imiquimod in 234 patients with LM, all from uncontrolled studies. A recent review evaluated 161 of these cases.2 However, the authors included highly variable types of studies (Table 7): case series, individual case reports, and open-label studies. There were also differences in lesion size and type (primary or recurrent), previous treatment, treatment regimens (from twice-weekly to daily applications) and duration (8 days-9 months), margin width, confirmation of treatment response (not always by biopsy), and follow-up times (shorter than the standard 5-year period used in oncology). Many of the studies had a follow-up time of less than a year.

Imiquimod is generally not recommended in invasive tumors or in young patients due to the risk of progression to invasive disease, or in patients who cannot be closely monitored.103,104

Imiquimod applied 5 times a week for at least 12 weeks has been proposed as the most effective treatment regimen. Response rates vary from series to series.104 While an 85% clinical response rate with histologic confirmation has been reported,91 in most cases evaluation was done by punch biopsy of a previously positive area.2 In 3 studies, after initial imiquimod treatment full tumor excision was achieved, with histologic clearance rates of 75%, 63%, and 53%.105–108 Progression to LMM was reported during treatment in 3 patients.5,109,110

Because of variations in study design, it is not possible to identify optimal parameters or predictors of treatment failure or absence of response.110,111

Imiquimod has been associated with a hypothetical risk of favoring tumor progression.103,112 One study showed that treatment efficacy was significantly related only to a moderate to severe clinical inflammatory response.113 Different strategies have been used to improve inflammatory response, including increasing frequency of application (twice a day) or using occlusion, cryotherapy, or tazarotene 0.1% in gel.110,114,115 Clinical response should not be used on its own to evaluate treatment response, as clinical and histologic findings may not match (Fig. 6). All lesions should be biopsied after treatment.116 In some cases, at least 3 months should be left before biopsy unless an inflammatory response is absent or abnormal pigmentation persists. Biopsies performed too soon are difficult to interpret because of the frequent presence of florid interface dermatitis. Several authors have proposed performing a second biopsy 1 or 3 years after treatment, as late recurrences have been described.110 As mentioned earlier, dermoscopy and CRM may be useful for monitoring response.

Figure 6.

A, Lentigo maligna melanoma (0.125-mm Breslow depth after diagnostic biopsy) on the forehead of a 94-year-old woman. B, Marked inflammatory response after 2 months of treatment. C, Residual grayish hyperpigmentation between the eyebrows after 3 months of treatment. Tumor persistence ruled out by histology.

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The adverse effects associated with imiquimod treatment are postinflammatory dyschromia, frequent erythema and edema, erosions, telangiectasia,110 superinfection, and reversible punctate keratopathy with reduced visual acuity in periocular lesions.117 Systemic effects include cytokine release syndrome (headache, gastrointestinal discomfort, fever, and general malaise). There have also been reports of vitiligo,110 herpes simplex infection, and elevated liver enzymes.118

The advantages of imiquimod are the same as those associated with other nonsurgical treatment modalities.

Disadvantages include the lack of standardized protocols and regimens and of clinical and histologic response criteria.111 Furthermore, residual hyperpigmentation following treatment may be confused with recurrence.119

In conclusion, the use of imiquimod should be reserved for cases in which surgery and other nonsurgical treatments such as radiation therapy are contraindicated, at least until further evidence is available on its efficacy and safety.7

Imiquimod can be used as adjuvant therapy before surgery to reduce tumor size108,113 or after surgery to treat extensive melanoma in situ around the lesion excised.120 Some authors have recommended its use in recurrent LM following conventional excision or Mohs micrographic surgery, in cases with positive margins (as adjuvant therapy), or to prevent recurrence.37,100,121,122

The authors declare that they have no conflicts of interest.