Clinical, Cosmetic and Investigational Dermatology Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Lentigo Maligna: Clinical Presentation and Appropriate Management This article was published in the following Dove Press journal: Clinical, Cosmetic and Investigational Dermatology Helena Iznardo 1, * Abstract: Lentigo maligna (LM) is a type of melanoma in situ that has distinctive character­ 1, istics regarding epidemiology, risk factors and clinical features. In addition, LM has a potential Cristina Garcia-Melendo * Oriol Yélamos 1,2 to progress to an invasive tumor with potentially aggressive behavior: lentigo maligna mela­ 1 noma (LMM). Overall, LM has a very good prognosis, whereas LMM has the same prognosis Dermatology Service, Hospital de la Santa Creu i Sant Pau, Universitat as other invasive melanomas with similar Breslow thickness. LM/LMM represents Autònoma de Barcelona, Barcelona, a challenging entity not only regarding the diagnosis but also regarding the management. Spain; 2Dermatology Service, Centro Diagnostic criteria are not well established, and there is an overlap of clinical, dermoscopic and Médico Teknon – Quirónsalud, Barcelona, Spain pathological features with other benign pigmented skin lesions such as lentigines, pigmented actinic keratoses or macular seborrheic keratoses. LM/LMM’s common appearance within *These authors contributed equally to photodamaged skin makes lesion border identification difficult. Wide excisions are often this work required, but since LM/LMM typically appears on cosmetically sensitive areas such as the face, sometimes large excisions are not possible nor desirable. In this sense, specialized approaches have been developed such as margin-controlled surgery or image-guided treatment using reflectance confocal microscopy. Other treatments for LM such as cryosurgery, imiqui­ mod, radiotherapy or photodynamic therapy have been proposed, although recurrence/persis­ tence is common. The current manuscript reviews extensively the published data regarding the diagnosis, treatment and management of both complex entities LM and LMM. Keywords: lentigo maligna, melanoma, lentigo maligna melanoma, dermoscopy, dermatoscopy, reflectance confocal microscopy, staged excision, Mohs surgery, imiquimod Introduction and Epidemiology Lentigo maligna (LM) is a type of melanoma in situ (MIS), recognized both by the American Committee on Cancer and the World Health Organization. Despite being classified as a type of MIS, LM has distinctive characteristics regarding epidemiol­ ogy, risk factors and clinical features. In addition, LM has a potential to progress to an invasive tumor with potentially aggressive behavior: lentigo maligna melanoma (LMM).1,2 The lifetime risk of progression from LM to LMM ranges from 5% to 50% and increases with time.3 Overall, LM has a very good prognosis, whereas LMM has the same prognosis as other invasive melanomas with similar Breslow thickness.4 Correspondence: Oriol Yélamos Regarding incidence, LM and LMM account for approximately 4–15% of all Dermatology Service, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de melanomas, representing up to 10–26% of head and neck melanomas, as they most Barcelona, C/Mas Casanovas 90, Block A, commonly present on these areas.4 They typically appear on chronically sun- 5th Floor, Module 3, Barcelona 08041, Spain damaged skin in elderly people, as opposed to the most common subtype of Tel +34 935537007 melanoma, the superficial spreading type, which typically occurs on areas acutely Fax +34 935537008 Email oyelamos@gmail.com exposed to UV radiation.5 Mean presentation age of LM/LMM ranges from 66 to submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 837–855 837 DovePress © 2020 Iznardo et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. http://doi.org/10.2147/CCID.S224738 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Iznardo et al Dovepress 72 years, approximately a decade older than for other MITF and TP53 have also been implicated in melanomas melanoma subtypes.1 Men are more likely to be diagnosed on sun-damaged skin.18 with LM/LMM, although in some series a predominance LM represents a challenging entity not only regarding in females has been observed.6,7 the diagnosis but also regarding the management. Incidence has increased over the past few decades: Diagnostic criteria are not well established, and there is Swetter et al8 found that LM was the most prevalent an overlap of clinical, dermoscopic and pathological (79–83%) form of MIS in North Carolina. In a recent features with other benign pigmented skin lesions such study in Catalonia (northeast Spain) with 4999 MM cases as lentigines, pigmented actinic keratoses and macular (282 cases of LM and 136 of LMM), a significant seborrheic keratoses.12,19 LM common appearance increase in incidence was observed during an 8-year within photodamaged skin makes lesion border identifi­ period, from 6.9% in 2000 to 13.1% in 2007. Several cation difficult and they often extend beyond what is factors may explain this increase such as increased visible with the naked eye. Wide excisions are often chronic sun-exposure. Because LM appears on chroni­ required, with appropriate surgical margins appearing to cally sun-exposed skin, there is a higher incidence in be around 9 mm on the trunk and extremities, and southern latitudes compared to northern latitudes (1.3 greater than 1 cm on the head and neck.20,21 However, cases/100.000 person-years in Australia vs. 0.8 cases/ sometimes these large excisions are not possible nor 100.000 person-years in the United States). Other factors desirable in cosmetically-sensitive areas such as the face. In this sense, margin-controlled surgery such as such as Fitzpatrick skin types and skin cancer awareness Mohs micrographic surgery or staged-excision offers must be taken into account as they can influence the the highest cure rates with the minimal scarring neces­ reported incidence of LM. This increase has been attrib­ sary to achieve curation. However, the location of LM/ uted to aging of the population and changes in sun LMM on the head and neck region and their often large exposure patterns,6–12 as well as lack of recognition of size frequently represent obstacles to these therapeutic LM as a distinct histologic subtype in the past.9 It must options. In addition, margin-controlled surgical techni­ be noted that the increase in the number of LM cases was ques are not always available since they require trained significantly higher than the increase of the invasive surgeons and dedicated facilities, thus limiting its avail­ ones, and mean Breslow thickness of LMM has remained ability. Other treatments such as cryosurgery, imiquimod, stable.7 radiotherapy and photodynamic therapy have been pro­ Risk factors associated to LM/LMM include increased posed in order to decrease morbidity and recurrence age, chronically sun-exposed areas of sun-damaged skin, rates. Furthermore, a wait-and-see strategy has also increased number of lentigines, increased number of acti­ been suggested in select patients such as patients with nic keratosis and history of previous keratinocyte ­ numerous comorbidities and patients with limited life carcinomas.13 Genetic conditions such as xeroderma expectancy. pigmentosum, oculocutaneous albinism, Werner syndrome The current manuscript reviews the published data on and porphyria cutanea tarda are also associated with LM.13 the diagnosis, treatment and management of LM/LMM. Larger size of LM has been proposed as a risk factor for transformation to LMM. Clinical Presentation The pathogenesis of LM/LMM is complex. Whiteman LM/LMM arises on chronically sun damaged skin predo­ et al14 proposed in 2003 that cutaneous melanomas arise minantly of the head and neck area, which hosts 78.3% of through 2 distinct pathways, with chronic solar exposure the cases22 and with the cheeks accounting for 53.7% of being responsible for LMM. Elder et al15 have recently the cases.23 expanded on this concept suggesting a new classification However, extrafacial LM/LMM can also be encoun­ of melanoma with different genomic characteristics. tered. According to a study analyzing 71 cases of LM,24 Contrary to the observed in superficial spreading mela­ extrafacial lesions account for 17.5% of all LM/LMM noma, BRAFV600E mutations are infrequent in skin with cases, with patients being significantly younger when com­ marked solar elastosis.16,17 Driver mutations in LMM pared to head and neck LM/LMM patients. Extrafacial include NF1, BRAFV600K, NRAS and KIT. In addition, LM/LMM is usually seen on the trunk in men or extremi­ gain- or loss- of function mutations such as CCND1, ties in women.25,26 838 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al Figure 1 Lentigo maligna(LM)/LM melanoma (LMM) clinical presentations. (A) LM presenting as a large irregularly pigmented patch in the forehead with central regression and ill-defined borders. (B) LM arising on the right cheek clinically simulating a seborrheic keratosis. (C) Large LM occurring on the nose and surrounded by chronically sun damaged skin. (D) Light brown patch with ill-defined borders in a fair-skinned individual corresponding to a LMM that can clinically be easily mistaken for solar lentigo. (E) Extrafacial LMM affecting the upper back presenting as an isolated large homogeneous brown patch with irregular borders. (F) Nodular melanoma arising on a previous LM (note the brown pigment surrounding the nodule corresponding to the in situ component). LM/LMM usually presents as a slowly growing isolated Wood’s Lamp large pigmented macule or patch with irregular borders. At The Wood’s light emits ultraviolet (UV) light in times it can have a discontinuous appearance on clinical a wavelength of 320–400nm with a peak irradiance at examination with ill-defined borders. Additionally, LM/ 365nm. Epidermal melanin absorbs most of the light LMM can also present as an amelanotic/hypomelanotic emitted from the Wood’s light with little reflectance, mak­ macule or patch, especially in fair-skinned individuals ing superficially pigmented lesions appear darker than the (Figure 1). Repigmentation of previous white or gray hair surrounding normal epidermis. may rise suspicion towards the possibility of LM in the Rather than for the diagnosis, Wood’s lamp is especially scalp, and it has been described as an early sign of LM.27 useful for estimating LM/LMM size – particularly areas of Because of this slow growth and sometimes hypome­ subclinical disease invisible to the naked-eye- and therefore lanotic presentation, it is not uncommon that LM/LMM becomes an essential part of physical examination.28 Wood’s diagnosis is delayed, with 48.8% of lesions being >10mm light examination has been demonstrated to be useful for in diameter at the time of biopsy.23 With time, LM may margin assessment of melanoma in situ (MIS) before evolve into papules, nodules or thick plaques which cor­ biopsy,29 and is particularly useful in determining margins respond to invasive foci thus becoming LMM and confer­ of LM/LMM before surgical excision.30,31 ring risk of metastatic disease (Figure 1). However, Walsh et al30 prospectively studied the accu­ The clinical differential diagnosis includes solar len­ racy of preoperative Wood’s light examination for margin tigo, seborrheic keratosis, lichen planus-like keratosis assessment of MIS after excisional biopsy. They con­ (LPLK) and pigmented actinic keratosis which are sum­ cluded that it is not reliable to assess subclinical disease marized in Table 1. with Wood's light in these patients since many false posi­ Non-Invasive Diagnostic Tools tive and false negatives can occur. This is not surprising Non-invasive imaging methods including Wood’s lamp, since surrounding photodamaged skin can harbor numer­ dermoscopy and reflectance confocal microscopy can ous activated melanocytes. Hence, this may limit Wood’s improve the diagnostic accuracy for LM/LMM, improve lamp utility to delineate the LM/LMM margins as these margin delineation, aid in biopsy site selection and also melanocytes either isolated or within benign lesions become an important tool for monitoring treatment. (seborrheic keratoses, pigmented actinic keratoses) may submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 839 DovePress Iznardo et al Dovepress Table 1 Lentigo Maligna (LM)/LM Melanoma (LMM) Differential Diagnosis: Clinical Presentation and Dermoscopy Clinical Presentation Dermoscopy LM/LMM47,151 Appears on chronically sun damaged skin (predominantly Polygons/rhomboids/zig-zag pattern (angulated lines) head and neck) Annular-granular pattern Pigmented macule or patch with ill-defined borders Asymmetric pigmented follicular openings Circle within a circle 152 Solar lentigo Multiple lesions Moath-eaten borders Brown papule/plaque Pseudonetwork Darker areas can be elevated or verrucous Comedo-like openings Diffuse opaque-brown pigmentation Lightbrown fingerprint-like structures Milia-like cysts Seborrheic Appears on the torso and face Milia-like cysts keratosis153–155 Multiple lesions Comedo-like openings Sharply demarcated brown-to-black papules/plaques Hairpin vessels Can have verrucous/rough texture Sharp demarcation and moth-eaten borders Fat fingers LPLK156,157 Solitary lesion Localized or diffuse annular granular pattern Slightly reddish papule/plaque with smooth or verrucous surface Appears on sun-exposed trunk and upper extremities Pigmented AK49,151 Predominantly on the face Annular pattern Scaly and rough surface Grayish short strikes and granules Pseudoreticular structures Grayish brown dots and globules White and evident follicles Scales Brown-to-gray rhomboidal lines (without invading follicular openings) Background erythema Abbreviations: LM/LMM, Lentigo maligna/lentigo maligna melanoma; LPLK, lichen planus like keratosis; AK, actinic keratosis. be highlighted as well. Also, it must be born in mind that When assessing facial LM/LMM it is important to take dermal melanin is not accentuated by the Wood’s light and into account that facial skin has numerous terminal hair may lead to false negatives regarding a deeper atypical follicles, sweat gland ostia, and attenuated rete ridges. melanocytic component.32 These special features in facial skin create a pseudo- network appearance: a structureless pigment area inter­ Dermoscopy rupted by nonpigmented adnexal openings.33–35 Dermoscopy is a non-invasive technique that allows for According to the third consensus conference of the the visualization of skin structures not visible to the naked International Society of Dermoscopy36 both metaphoric eye and therefore improves diagnostic accuracy for both and descriptive terminology can be used to describe lentigo pigmented and non-pigmented skin lesions. Dermoscopy maligna dermoscopy. LM/LMM dermoscopy will be briefly consists of a handheld magnifier lens (normally around discussed herein by using metaphoric and descriptive termi­ 10x) which is coupled to a light source that can be polar­ nology, as well as their histopathological correlates. ized or non-polarized. Polarized and non-polarized dermo­ scopy provide complementary information for the Annular-Granular Pattern diagnosis of LM/LMM and it has been found to be super­ Dots and structureless brown to blue-gray areas scattered ior to Wood’s lamp examination to delineate the borders of throughout the lesion or arranged adnexal openings LM/LMM.28 (Figure 2A). Brown dots correspond on histopathology to 840 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al Figure 2 Lentigo maligna(LM)/LM melanoma (LMM) dermoscopic findings. (A) Facial LM with an annular-granular pattern consisting of brown dots scattered around adnexal openings. (B) LM showing a large blotch with the blue-black sign. (C) LM on the scalp with follicle obliteration and central regression (gray peppering or granularity). (D) Facial LM with an annular-granular pattern around adnexal openings and follicle obliteration. (E) Brown lines coalescing to form rhomboids (angulated lines) around adnexal ostial openings at the periphery of this LM. Also, an asymmetric distribution of pigment surrounding the follicular openings can be seen. (F) Extrafacial LM with presence of network and atypical dots. Note the absence of adnexal openings in extrafacial skin. aggregates of melanocytes and small nests at the dermoe­ especially in LM located on the lower part of the face23 pidermal junction between the follicles. Blue-gray granu­ (Figure 2). A fine circle, semicircle, signet ring-like circle, larity corresponds to melanophages in the upper dermis. irregular circle and double circle can be seen. On histopathology, it corresponds to atypical melano­ Polygons/Rhomboids/Zig-Zag Pattern (angulated cytes as single units or small nests in the epidermis that are lines) surrounding and/or extending down hair follicles.35 They correspond to gray-brown lines that are connected at an angle or coalescing to form polygons (Figure 2E). The Circle Within a Circle term “rhomboids” was introduced to describe gray-brown When concentric pigmented circles surrounding follicular angulated lines around adnexal ostial openings in LM. openings are present it is called the circle-within-a-circle This term is reserved for facial skin, and they are more structure, which is identified in 5% and 25.4% of frequently seen in LM located on the upper part of the cases.23,41,44 face.23,36,37 However, the term “zig-zag pattern” can be Regarding extrafacial LM/LMM, the most common regarded as a variant of rhomboids on facial skin.38 dermoscopic structures are granularity (67.7%), angulated Whereas the terms “rhomboids” and “zig-zag pattern” are lines (44.1%), and atypical dots (36.6%).45 However, reserved for facial skin, angulated lines39 and polygons40 are because of preserved rete ridges and significantly fewer the appropriate terms to characterize pigmented lines that adnexal openings in extrafacial skin, focal islands of net­ form angles in melanomas on nonfacial skin,39,41 although work without an annular granular pattern can be many use “angulated lines” as a single term that encompasses observed46 (Figure 2F). polygons and rhomboids, regardless of their location. Schiffner et al33 described a model of the dermoscopic These structures correspond histologically to confluent progression for LM/LMM (Figure 3). Initially, asymmetric junctional atypical melanocytes together with underlying pigmentation and dots around the follicle are seen, which melanophages in the papillary dermis.33,42,43 later evolve to rhomboidal structures and finally form homogeneous pigmented areas and cause obliteration of Asymmetric Pigmented Follicular Openings the follicular openings. Pralong et al47 found that at least The presence of asymmetric distribution of pigment sur­ one of the structures previously described are present in rounding the follicular openings is characteristic, 87% of LMM. The combination of asymmetrically submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 841 DovePress Iznardo et al Dovepress Figure 3 Schiffner progression model fo LM/LMM. Initially asymmetric pigmentation and dots around the follicle are seen (A), which later evolve to rhomboidal structures (B) and finally form homogeneous pigmented areas and cause obliteration of the follicular openings (C). Adapted with permission from Dermoscopedia (https:// creativecommons.org/licenses/by-nc-sa/4.0/).158 pigmented follicular openings, gray dots, gray globules, or from other pigmented lesions in the face. These features rhomboidal structures located anywhere within a lesion include scales, white follicles, erythema/reticular vessels, has a sensitivity of 89% and a specificity of 96% for reticular and/or curved lines/fingerprints, structureless LM/LMM.33 Another diagnostic clue for LM/LMM diag­ brown color, sharp demarcation and classic criteria of sebor­ nosis is the darkening at dermoscopic examination.47 In rheic keratosis. If no prevalent non-melanoma patterns are fact, in 25% of LM/LMM the pigment appears darker and seen then the suspicion for melanoma increases. with different shades of brown and gray when viewed with dermoscopy compared to naked-eye examination.47 Reflectance Confocal Microscopy Moreover, it should be taken into account that increased Reflectance confocal microscopy (RCM) is a non-invasive density of the vascular network within the lesion when imaging tool that uses near-infrared laser light obtaining compared to adjacent skin is found in 58% of cases,47 and horizontal quasi-histological images.52 RCM improves diag­ should rise suspicion for invasive melanoma.48 nostic accuracy of multiple skin tumors.52,53 It is very useful for diagnosing and monitoring LM/LMM since it has cellu­ Differential Diagnosis lar resolution and allows the visualization of very small It must be born in mind that gray color, gray circles, and amounts of melanin which are invisible to the naked eye or annular granular structures can be seen in both pigmented dermoscopy.52 Therefore, RCM is an ideal tool to differenti­ actinic keratoses (PAK) and LM/LMM. Similarly, the ate LM/LMM from benign macules and solar damage.54,55 hyperpigmented rim of follicular openings of LM/LMM RCM increases the physician’s diagnostic confidence can be mistaken for pseudofollicular openings of sebor­ and increases diagnostic sensitivity, therefore improving rheic keratoses.49 The differential diagnosis among these the management of difficult lesions.53 In fact, RCM is entities is further assessed in Table 1. more sensitive (overall sensitivity of RCM 0.93) and spe­ Some algorithms have been proposed to differentiate cific (overall specificity 0.89) than dermoscopy (overall pigmented lesions of the face. sensitivity 0.73, and overall specificity was 0.84) for the Micantonio et al50 proposed an algorithm to distinguish diagnosis of LM.56 Moreover, the integration of dermo­ between facial LM and PAK with an excellent accuracy and scopy and RCM increases the diagnostic accuracy of both a high positive predictive value for early facial LM. Eight these techniques used alone for facial tumors.57 dermoscopic criteria achieved the highest discriminative RCM is remarkably useful when assessing lesions power to distinguish LM from PAK: light brown color, located on the head and neck area,58 and is particularly brown-to-gray incomplete circles, brown-to-black structure­ suitable for the identification of hypomelanotic/amelanotic less zone obscuring the hair follicles, structureless brown and recurrent LM/LMM.59,60 eccentric zone, structureless blue zone, brown-to-black struc­ Menge et al found the RCM and histopathology results tureless zone, in-focus brown discontinued lines and scales. were consistent in 89% of the cases when evaluating Tschandl et al51 focused on the evaluation of non-melanoma suspected LM, but skin damage may limit the specificity dermatoscopic features in order to differentiate LM/LMM of the diagnosis.61 842 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al Figure 4 Reflectance confocal microscopy images of a lentigo maligna. The epidermis (depth ~50 µm) shows numerous pleomorphic pagetoid cells composed of large round cells (arrowheads, A) as well as dendritic cells (star, A), which can invade the hair follicles (star, B). At the dermal-epidermal junction (depth ~150 µm), one can also identify disarrangement of the basal layer as well as large plump cells which correlate with melanophages (arrowhead, B), and junctional thickenings than can radiate from the hair follicles adopting a medusa head-like () structure (arrowhead, C), or a mitochondria-like structure (asterisk, D). (white scale bars: 250 µm). The proliferation of atypical melanocytes at the DEJ of 2 major and 4 minor criteria, represented in Table 2. may be visualized on RCM as atypical round or dendritic A LM score of greater than 2 resulted in a sensitivity cells, typically large (twice the size of the adjacent of 85% and specificity of 76% for the diagnosis of LM, keratinocytes)59 (Figure 4). As LM becomes more exten­ and the algorithm was equally effective in the diagno­ sive, pagetoid spread of large pleomorphic cells are seen sis of amelanotic lesions. Some of the features included through all layers of the epidermis, causing epidermal in the algorithm are the presence of round and large disarray. Poorly defined dermal papillae and atypical pagetoid cells and the presence of more than three cells may be seen at the dermal-epidermal junction and atypical cells at the dermoepidermal junction in five can form bridges resembling mitochondrial structures.62 images. However, Champin et al65 consider that the Other characteristic findings include junctional swelling presence of a single large bright dendritic cell- with infiltration of the hair follicle, resembling caput predominantly found around follicle openings – should medusae (Figure 4), which was found to be indicative of be considered part of the tumor when assessing LM LM/LMM compared to nonmelanocytic skin neoplasms, margins. Moreover, Yélamos et al66 believe atypical with an overall sensitivity of 96% and specificity of melanocytes continuing from the center of a LM/ 83%.59,63,64 LMM, regardless of their size, should be considered Guitera et al59 developed a LM score to distinguish as positive for LM as they may reflect the trailing edge LM from benign lesions of the face. The score consists of a LM/LMM (Table 2). submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 843 DovePress Iznardo et al Dovepress Table 2 In vivo Confocal Features for LM Diagnosis Future Directions Guitera et al, 2010 (LM Score) 59 Machine learning (ML) is a form of artificial intelligence which uses computer algorithms to help with clinical deci­ Major features (2 points each) ● Nonedged dermal papillae sions. An interesting subfield of ML is deep learning, in ● Round and large pagetoid cells (>20 microm) which large datasets are scaled, allowing to improve them­ Minor features (1 point each) selves with more data.71 Deep learning convolutional neural ● More than three atypical cells at the dermoepidermal junction in networks (CNNs) have further improved the accuracy of ML five images in melanoma screening, even exceeding some ● Follicular localization of pagetoid cells ● Nucleated cells within the dermal papillae dermatologists.71,72 These algorithms could improve LM/ Minor negative feature (1 point) LMM diagnosis in the future,73 although some limitations ● Broadened honeycomb pattern have to be addressed. Winkler et al74 investigated the diag­ Champin et al, 201465 nostic performance of a CNN across different melanoma subtypes, including LMM. The authors used ● Single large round cell or large dendritic cell a dermatoscopic image set containing 30 LMM and 100 Yélamos et al, 201766 benign lesions (flat, macular solar lentigines, seborrheic ● Atypical dendritic cell (any size) continuing from the LM trailing edge. keratoses and nevi), matched for localization and morphol­ ogy. A “malignancy score” ranging from 0 to 1 (higher scores indicating a higher probability of melanoma) was RCM is also useful for margin definition in ill-defined obtained by the CNN. Average score was 0.98 for LMM lesions45 and to map the extent of LM/LMM before and 0.37 for solar lentigines, seborrheic keratoses and nevi. treatment.67,68 Champin et al65 described a new procedure Sensitivity and specificity (95% confidence interval) for that combined the “spaghetti” technique (described in the diagnosis of LMM (a priori cut-off of >0.5) was 100% treatment section) with in vivo RCM to evaluate LM margins, (88.7–100%) and 65.0% (55.3–73.6%), respectively. These with better results than with the “spaghetti” technique alone. good results are promising, although the authors admit that Handheld RCM (HRCM) together with the use of their dermatoscopic images were of greater quality than videomosaics (static mosaics obtained from dynamic those obtained in a clinical routine setting. In addition, videos) has allowed an accurate evaluation of large most images were derived from fair-skinned patients. lesions in curved areas of the body, including the face. Images of LMM in individuals of other ethnic background HRCM has been reported to be useful for detecting are scarce, therefore these can suppose additional limitations subclinical margins, and presence of invasion,69 thus for pattern recognition by CNNs. In addition, some charac­ becoming a valuable tool for deciding the optimal treat­ teristics of pigmented skin lesions make them unavailable ment. Yélamos et al66 combined adhesive rings and for ML analysis.75–77 The most relevant is the difficulty in radial videomosaics obtained with HRCM to calculate assessing the border of the lesion (lack of pigmentation, lack clinical extension and presurgical margins of LM/LMM, of surrounding normal skin, presence of hair and lesions and to identify LM/LMM extending beyond the dermo­ appearing in volar skin). Another important limitation is scopic and Wood’s lamp margins showing excellent large lesions that do not fit into the field of view of the accuracy when compared to margin-controlled surgery dermatoscopic camera. In addition, a recent study78 evalu­ using staged excision. ated the limitations in image selection for ML analysis. A prospective study evaluating the correlation of Authors found that 66.7% of the LM included in the study LM/LMM subclinical extension defined by RCM com­ showed exclusion criteria, with only 33.3% of them being pared to the gold standard histopathology showed an eligible for ML analysis.78 Therefore, although ML and overall agreement of 85.9% between RCM imaging CNN will probably play an important role in the future and histopathology of staged excision margins.70 management of LM/LMM, there are still limitations that Diagnostic accuracy for detection of residual melanoma need to be addressed by the use of larger image datasets in the tumor debulking (after biopsy) had a sensitivity of that better represent different skin types, include benign 96.7% and a specificity of 66.7% when compared to the lesions as well as images obtained with consumer cameras histopathology. in a rather uncontrolled manner. 844 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al Histopathology Histopathology Analysis Biopsy Technique The diagnosis of LM/LMM is usually made by histopatholo­ When a lesion has been identified as suggestive of LM/ gic examination. The dermis may show solar elastosis1 and LMM, a skin biopsy typically allows for a definitive diag­ may display a patchy or band-lymphocytic infiltrate. Some nosis. Different biopsies can be performed regarding the authors suggest that the presence of melanophages is a helpful purpose (incisional/excisional) or the technique (shave/ to differentiate LM from melanocytic hyperplasia of chroni­ punch/ellipse). The choice between one or another cally sun-damaged skin.86 The epidermis of LM/LMM is depends on the size of the lesion, location, cosmesis and often atrophic and it can have hyperpigmentation of basal patient’s and physician’s preferences. keratinocytes.4,87 It is important to highlight that no histologi­ Agarwal-Antal et al80 reported that 16% of LM contain cal differences have been found between facial and extrafacial invasive melanoma. Diagnostic excisional biopsy with LM/LMM.88 narrow margins has been considered the gold standard Initially, LM is characterized by an increased density for diagnosing melanoma because incisional biopsy can of melanocytes along the dermal-epidermal junction, underestimate the depth of the lesion due to sampling although they may also be found in the spinous layer1 error.81 Also, a broad shave biopsy extending into the (Figure 5). These melanocytes can have variable nuclear deep papillary dermis or superficial reticular dermis can atypia1 and can show dendritic appearance.89 Some mela­ be acceptable for LM/LMM since it allows the evaluation nocytes can be multinucleated and have prominent dendri­ of a large piece of tissue.82,83 tic processes, known as “starburst giant cell”,90 which is However, RCM enables the physician to assess the not specific for LM and can also be seen in benign mela­ invasive components of LMM and target biopsies to the nocytic nevi.91 The adnexa can be involved by neoplastic thickest areas, thus potentially reducing sampling error.68 melanocytes,92 and is first seen in the infundibular part of In a retrospective study by Mataca et al,84 RCM selected the follicle. At the next stage, pagetoid spread, melano­ sites showed more histopathologic criteria when compared cytes with hyperpigmented and angulated nucleus in the to dermoscopy selected sites. basal layer, and involvement of the deeper portion of the HRCM can guide mapping biopsies by detecting fea­ follicles can be seen.93 tures of LM with high sensitivity, thus reducing sample Regarding LMM, some histologic variables have been bias inherent to blind mapping biopsies.67 Also, mapping identified. These include melanocytes forming rows, sub­ of LM/LMM with HRCM-videomosaicing can reduce the epidermal clefts, a lesser degree of solar elastosis and number of biopsies needed in doubtful areas.69 nests.94 Nests of pleomorphic melanocytes – resembling Figure 5 (A) Histological pictures of lentigo maligna. Lentigo maligna in the radial growth phase. Solar elastosis (arrow), a patchy lymphocytic infiltrate and melanophages are seen in the dermis (+ sign). An atrophic epidermis (asterisk) and an increased density of melanocytes along the dermal-epidermal junction can be seen, some of them with variable nuclear atypia (arrowheads). Hematoxylin-eosin stain10x. (B) Extrafacial lentigo maligna on chronically sun-damaged skin. Atrophic epidermis (asterisk), prominent solar elastosis (arrow) and increased density of junctional pleomorphic melanocytes forming asymmetric nests with pagetoid growth of single melanocytes (arrowheads). Dermal inflammatory infiltrate with melanophages (+ sign). Hematoxylin-eosin stain10x. submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 845 DovePress Iznardo et al Dovepress dysplastic junctional nevus – predominate in 43% of LM/ Surgical Excision LMM.95 Current guidelines suggest that surgical excision is the treat­ The vertical growth phase often shows spindle cell ment of choice for both LM and LMM.81 The primary goal of morphology. Up to two-thirds of desmoplastic melanomas surgical excision of LM/LMM is to achieve histologically- are associated with LM,96 and neurotropism is not uncom­ negative margins and prevent local recurrence because of mon in deeply invasive LMM86 Immunohistochemical persistent disease, as stated by the latest guidelines for the markers such as MART-1 may help identify a dermal treatment of melanoma published by the American Academy invasive component. of Dermatology and the National Comprehensive Cancer Network.81,101 Therefore, a surgical excision technique that Treatment carefully examines the entire tumor to exclude areas of inva­ Even though LM has good prognosis, treatment is necessary sion and complete surgical margins for accurate tumor clear­ in order to reduce the potential for LMM transformation ance must be chosen.102 A standard elliptical wide excision and its associated mortality. The classic treatment which examines a very small percentage of the total margin, with remains the mainstay is surgical excision with safety mar­ the risk of false-negative margins increasing as the number of gins. However, due to the cosmetically-sensitive location on bread loaf sections decreases. Margin-controlled surgical sun-exposed areas such as the face, surgery is not always techniques such as staged excision or Mohs micrographic possible or desirable. Herein we will review the different surgery offer low recurrence rates of 0.5% to 5%, and they treatment modalities with their grades of recommendation also provide tissue-sparing in these cosmetically-sensitive and levels of evidence (Table 3).81,97 A big limitation is that sites.102 there have been no randomized controlled trials to date comparing the efficacy of all LM treatments. Treatment Conventional Surgery choice is complex and depends on factors such as anatomic The conventional melanoma margins of 5 mm for in situ location and previous treatments, as well as patient comor­ disease and 10 mm for invasive disease have been demon­ bidities, age and treatment adherence.98 In fact, Fosko et al strated to be inadequate in LM and LMM,21,81,102–104 have proposed a personalized treatment plan in which especially in the head and neck region. Kunishige et al21 patients with no comorbidities are suited for surgical exci­ observed clearance rates of 79.4%, 94.4%, 97.4% and sion, whereas patients who do not tolerate surgery are 98.7% for 6, 9, 12 and 15 mm margins, respectively, in offered off-label imiquimod or radiotherapy.99 Patient care overall LM. Microscopic assessment of LM is difficult would benefit from a multidisciplinary team composed by because adjacent actinically damaged skin frequently dermatologists, surgeons and both medical and radiation shows actinic melanocytic hyperplasia, which can simulate oncologists.100 atypical junctional melanocytic proliferations.105 Table 3 Evidence-Based Recommendations for Lentigo Maligna (LM) Strength of Level of Recommendation Evidence Complete surgical removal of LM with 5- to 10-mm clinical margins is the preferred management, when C III possible Peri-operative reflectance confocal microscopy margin assessment should be considered when available C III Mohs micrographic surgery is recommended for LM when available B II/III Topical imiquimod 5% cream as second-line treatment for LM when surgery is not possible at the outset B II/III (primary setting) or when optimal surgery has been performed (adjuvant setting) Radiotherapy as a second-line therapy for nonsurgical candidates C II/III Superficial brachytherapy is not recommended C III Cryotherapy is not recommended C III Laser therapy is not recommended C III Notes: Adapted from Swetter et al81 and Robinson et al.97 Strength of Recommendations. A. Recommendation based on consistent and good quality patient-oriented evidence. B. Recommendation based on inconsistent or limited-quality patient-oriented evidence. C. Recommendation based on consensus, opinion, case studies, or disease- oriented evidence. Level of Evidence. I: Good-quality patient-oriented evidence (ie, evidence measuring outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life). II. Limited-quality patient-oriented evidence. III. Other evidence, including consensus guidelines, opinion, case studies, or disease-oriented evidence (ie, evidence measuring intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes). 846 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al Mohs Micrographic Surgery (MMS) Alternative minimally-invasive treatments have been pro­ It consists of excision of the lesion with immediate micro­ posed in LM in order to decrease morbidity and recurrence scopic frozen section examination of 100% of the peripheral rates. The greatest limitation of all these techniques is that and deep excision margin. The main limitations are its high LMM cannot be completely excluded, as the whole speci­ costs, that it’s a time-consuming technique, and that histolo­ men is not examined histologically. gic interpretation of melanocytic atypia is difficult since Cryotherapy with liquid nitrogen (cryosurgery) is an freezing leads to artefactual changes in the melanocytes.106 alternative approach in select patients, with recurrence Sensitivity and specificity rates for diagnosing LM/LMM on rates ranging between 0% and 40%.113,114 Melanocytes frozen sections vary from 100% and 90% to 73% and 68%, are highly sensitive to low temperatures, being destroyed respectively.107,108 However, immunohistochemical stains between −4 and −7ºC.115 A depth of at least 3 mm must be such as MART-1 or MITF can be used in frozen sections, achieved in order to destroy atypical melanocytes that may thus improving the diagnostic accuracy. Local recurrence have extended into the hair follicles.116 Study comparison rates for melanoma treated with MMS with MART-1 are is limited by variability in treatment regimens and duration between 0.2% and 0.49%.109,110 If tumor is detected at the of follow-up. A study with 18 patients with LM used two margin, targeted excision or a second stage is performed freezing cycles of 1 minute each, separated by a thaw around the residual tumor, repeating the process until clear cycle of at least 2 minutes, with frozen areas extending margins are achieved. A recent systematic review including 1 cm beyond the borders of the lesions.117 No recurrences 27 articles showed a 1.35% recurrence rate with MMS.111 or metastasis were observed during a mean follow up of Another potential benefit of MMS is that LMM can be 75.5 months.117 detected prior to reconstruction, allowing accurate sentinel lymph node biopsy (SNLB) prior to complex reconstructions Immunocryosurgery that would otherwise compromise SNLB. In addition, some Combination of cryosurgery sessions with imiquimod authors advise that the central tumor debulking specimen application has been successfully used for LM. This should be sent for formalin-fixed paraffin embedded sections, method increases local inflammation and therefore the to detect possible invasion and eventual LMM upstaging.112 effectiveness of the treatment in those patients who do not respond with vivid inflammation to imiquimod Staged Excision alone.118 Different regimes have been applied with vari­ This technique is a variation of MMS and allows confir­ able results. Matas-Nadal et al119 used topical imiquimod mation of negative margins with delayed repair of the 5% cream once daily on the lesion plus 1 cm along the surgical site. The usual procedure involves vertical exci­ lesion edge for 3 weeks, followed by one session of sion with initial narrow margins examined by formalin- cryosurgery (2 cycles of 20 seconds) on the lesion plus fixed permanent sections. Further excision is guided by 1 cm along the lesion edge. This was followed by 6 histology over subsequent days. A variation of this techni­ months of topical imiquimod cream 3 times per week. que which only assesses a rim of peripheral tissue has also Clinical clearance was observed in 3/3 patients. been described and named “spaghetti technique”. A correlation with increased lesion size and with recurrent Imiquimod lesions and increasing surgical margin required for tumor Imiquimod is a topical immune-response modifier that acts clearance has been found with staged excision.102–104,112 through binding Toll-like receptors 7 and 8 on dendritic cells, Margin-controlled surgical techniques require an macrophages and neutrophils, recruiting CD68+ macro­ expert multidisciplinary team formed by expert dermatol­ phages and cells involved in cytotoxic T cell responses.120 ogists, Mohs micrographic surgeons and pathologists with In addition, it may interfere with adenosine receptor path­ close communication and clinical-pathological correlation ways, increasing adenylyl cyclase activity; and may have that is only achievable in referral centers.100 proapoptotic activity against tumor cells.13,121 Although it is off label, topical 5% imiquimod cream for LM has been Non-Surgical Treatment extensively used, with variable results.122–125 Complete his­ As stated before, LM common location on the head and topathologic responses (based on targeted biopsies) range neck region, big size and advanced age of the patients from 50% to 93%, recurrence rates range from 7.1% up to frequently represent obstacles to surgical treatment. 50% and mean follow-up durations range from 6 months to submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 847 DovePress Iznardo et al Dovepress 4.5 years.122–126 Once again, variability in treatment regimes, development of LMM after imiquimod treatment for LM assessment of outcome and duration of follow-up make has been described.129,131 Whether imiquimod had a role comparison between studies difficult. The inability to elim­ in tumor progression or focal microinvasion was already inate atypical melanocytes within hair follicles due to limited present in these lesions is unknown. penetration has been proposed as an important limiting factor Advantages of imiquimod include superior cosmetic for imiquimod’s higher recurrence rates.81 A recent study has result, home application, avoidance of surgical morbidity, investigated the role of the host immune response in order to and treatment of potential atypical melanocytes in sur­ identify responders to imiquimod.127 Samples were taken rounding skin. However, the main limitation of this treat­ prior to starting imiquimod 5 days per week for 12 weeks. ment is the potential severe inflammatory reactions At 16 weeks, lesions were excised and assessed histologi­ observed. However, these adverse effects are usually lim­ cally. No differences between immune cell subset densities ited to dose-dependent local skin reactions that subside were observed between responders and non-responders pre- after stopping of treatment, and post-inflammatory pig­ treatment. Post-treatment, responders showed up-regulated mentation. Systemic side effects, although rare, have antigen presentation, type I interferon, T cell activation and been described and include flu-like symptoms. The latest tolerance induction signaling pathways.127 The optimal regi­ American guidelines for the treatment of melanoma con­ men treatment remains to be determined, but a typical regi­ sider imiquimod as a second-line treatment for LM when men is an application for 5–7 days per week for 12 weeks, surgery is not possible (primary setting) or when optimal within a 1–2cm margin of clinically normal-appearing surgery has been performed (adjuvant setting), after care­ skin.124 A systematic review with 471 patients treated with fully discussing of its limitations and associated risks with imiquimod in different treatment schedules observed that the patient and family.81 a treatment schedule using 6–7 applications per week, with at least 60 applications total, had the greatest odds of com­ Radiotherapy plete clinical and histological clearance of LM.128 Radiotherapy (RT) can be used in LM as primary treatment Imiquimod as a neoadjuvant therapy has also been used or as adjuvant treatment when positive margins are found in LM, demonstrating to be useful for decreasing the after surgery. The latest American guidelines for the treat­ necessary margin for complete clearance.121,129 In ment of melanoma support the use of radiotherapy for LM as a study with 334 patients treated with imiquimod 5% a primary treatment when complete surgical excision is not cream 5 nights per week for 2 to 3 months followed by possible81 and the European Society of Medical Oncology staged excisions, there was a median final margin of 2 mm states that “RT for local tumor control should be considered with a recurrence rate of 3.9%, a mean time to recurrence in cases of inadequate resection margins of LMM”. of 4.3 years and a mean length of follow-up of 5.5 Superficial RT (Grenz ray or Miescher technique) was initi­ years.121 Addition of tazarotene 0.1% gel to imiquimod ally used, with recurrence rates ranging from 7% to 12% in 2 cream 5% prior to staged excision has been assessed in large retrospective studies.132,133 However, this modality is a randomized trial of 47 patients in order to improve not preferred currently due to insufficient dermal penetration imiquimod’s response.129 Complete response after 12 of Grenz rays (1 mm into the dermis) and therefore lack of weeks was observed histologically in 78% of lesions trea­ adnexal treatment, where residual atypical melanocytes can ted with combined therapy versus 64% treated with mono­ remain.134 A different approach with a slightly deeper pene­ therapy (p = 0.17). Residual LM was observed in 22% of tration has been increasingly used, with reported cure rates of the lesions treated with combined therapy versus 36% with 86–91%.135 A concern with deeper penetration is scarring monotherapy on subsequent staged excision, without and pigmentary changes, which may be difficult to differ­ recurrences at a mean follow-up of 42 months.129 entiate from recurrence. A literature review including 349 Assessment of treatment response is complicated irradiated patients found a crude 5% LM recurrence rate, although RCM may be useful (as discussed later in the with a median study follow-up of 3 years.136 Resolution of section “management”). Clinical inflammation is generally pigmentation occurred after 2–24 months in the same review. associated with adequate histologic response, although Differing treatments, parameters, and dosages limit specific there are cases in which this was not observed and actually recommendations. The field should be expanded 1 cm showed the opposite results (inflammatory reaction with­ beyond the area marked as involved by RCM.136 Another out histopathologic clearance).129,130 In addition, the systematic review examined 10 studies with a total cohort of 848 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 DovePress Dovepress Iznardo et al 454 patients treated with RT. Complete response rates varied at 150 μg/g daily for 3 days has been published, with between 80% and 100%, and mean recurrence rate was of disappointing results. Only 2 achieved complete response 11.5%.137 Regarding electronic surface brachytherapy, it is and no correlation between ingenolol mebutate-induced not recommended by the latest American guidelines for the inflammation and clinical/histological clearance was treatment of melanoma.81 A multicenter-randomized trial of observed.144 imiquimod versus definitive RT is currently active and will provide results in the following years (NCT02394132).134 Other Non-Surgical Treatments Photodynamic Therapy Other treatments such as azelaic acid, intralesional inter­ Photodynamic therapy (PDT) is an effective, non-invasive feron alpha, fluorouracil and retinoids have proven to be treatment for precancerous and cancerous skin lesions. ineffective for the treatment of LM and therefore are not Studies have shown that PDT with 5-aminolaevulinic acid currently recommended.27 induces in vitro lysis of melanocytes.138 Karam et al139 trea­ ted 15 LM with PDT with methyl-aminolaevulinate, achiev­ Monitoring ing a cure rate of 80% (12/15). They used a higher light dose Monitoring is crucial in order to detect persistence, recur­ (average 60 J/cm2) than the dose for non-pigmented carcino­ rence or progression in treated LM/LMM patients. The mas (37 J/cm2), as melanin restricts the diffusion of red light mean time to local recurrence of primary LM and thin into deep layers of the epidermis. The response was assessed LMM was identified to be at least 57.5 months.145 The by clinical follow-up (18–50 months) and multiple surgical cure rate is considered after 5 years; therefore, biopsies.139 A recent study investigated the efficacy of abla­ a long term follow-up is required. Surgery and other non­ tive fractional laser-assisted PDT (average dose 90 J/cm2) surgical treatments can cause inflammation, pigmentation with 5-aminolaevulinic acid nanoemulsion for treating and scarring which should be taken into account when LM.140 The rationale for using ablative fractional laser is assessing treated LM/LMM. Also, identifying local recur­ that it allows for the photosensitizer precursor to penetrate rence can be challenging in patients with chronically sun deep enough to reach all the atypical melanocytes. Seven out damaged skin. of ten lesions (70%) were histologically completely cleared Clinically, recurrent/persistent LM/LMM can be iden­ after three sessions. These promising results suggest that tified by the onset of a papule, nodule or change over PDT could be an alternative therapy for inoperable LM.140 a treated area, which typically tends to be amelanotic or lightly pigmented with nonspecific clinical and dermo­ Laser Therapy scopic features.146 Dermoscopy can sometimes improve Besides the use of fractional lasers to increase the penetra­ the detection of recurrence/persistence and assist in post- tion of PDT, described in the previous section, various treatment monitoring. The presence of “dust-like dots” is forms of laser therapy have been used for the treatment a clue for treatment failure in cases of LMM treated with of LM, with the majority of evidence derived from anec­ imiquimod or radiotherapy.146 dotal reports and case studies. Carbon dioxide, Q-switched Follow-up after treatment can also be assisted by ruby, argon, neodymium-doped yttrium aluminium garnet, RCM. It is recommended to wait at least 3 months after alexandrite laser or combinations of the above have shown surgery to assess the treated area with RCM to avoid poor results, with high recurrence rates.137 Lee et al inflammation and early scarring changes.147 HRCM has reported a recurrence rate of 6.7% for carbon dioxide been reported to be useful for detecting persistence or laser (1/15), with an initial response of 100%.141 Further studies with accurate treatment protocols are needed to recurrence of LM/LMM, and also for monitoring after confirm these results. surgical and nonsurgical treatment,148 especially in large, amelanotic or poorly pigmented lesions.68 Ingenol Mebutate Alarcon et al149 found no statistically significant differ­ Although ingenol mebutate has shown to induce apoptosis ences between RCM and histopathology when evaluating in melanoma cells in vitro,142 clinical data are nonconsis­ the response of LM to imiquimod. RCM identified 70% of tent. One case reported its efficacy in a 91-year-old patient patients as responders to imiquimod without false-negative with a recurrent LMM.143 Recently, a prospective multi­ results, whereas response was overestimated with clinical center study with 12 patients treated with ingenol mebutate evaluation and underestimated when using dermoscopy. submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2020:13 849 DovePress Iznardo et al Dovepress Clinical follow-up and examinations frequency depend monitoring after treatment with ancillary tests such as on the AJCC primary tumor stage and the presence of dermoscopy of RCM is fundamental, to exclude and additional risk factors, such as family history of mela­ identify persistent or recurrent disease. Randomized clin­ noma, history of sunburns, dysplastic nevi, among others. ical trials comparing the efficacy of different treatments, LM tends to have a slower growth compared to other including surgical and minimally-invasive, are needed to subtypes of melanoma; however, when LM transforms provide evidence-based data to improve the management into LMM and therefore becomes invasive, its prognosis of this challenging skin cancer. and management are the same as the other melanoma subtypes. According to the latest 2019 European melanoma Disclosure Dr Oriol Yélamos reports personal fees from Leo Pharma and guidelines,150 follow-up for recurrence detection should Almirall, outside the submitted work. The authors report no be performed for at least 5 years, and follow-up for the other potential conflicts of interest for this work. detection of new melanomas and other skin cancers for at least 10 years. 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