BACKGROUND

Lentigo maligna (LM) is a melanocytic neoplasm that occurs on chronically sun-exposed skin and is mainly seen in middle-aged and elderly patients (Koh et al., 1984). It is now widely accepted that LM represents the in situ phase of LM melanoma (LMM), and its prognosis is directly related to the depth of invasion, mitotic rate, ulceration, and other adverse features (Iznardo et al., 2020). Risk factors for the development of LM include a history of sunburns, a history of nonmelanoma skin cancers, older age, lighter skin types, and a tendency to form solar lentigines (Naik, 2021). The rates of LM in non-Hispanic Black populations are so low that the Centers for Disease Control and Prevention excluded this population when identifying survival rates by melanoma subtype (Culp & Lunsford, 2019). This is not to insinuate that LM does not occur in skin of color patients, and future research should identify how LM presents in this patient population. In contrast to other types of melanomas, LM is associated with higher rates of p53 mutations compared with BRAF mutations and lacks the genetic propensity to form atypical nevi (Xiong et al., 2022).

PATHOGENESIS

LM arises from DNA mutations secondary to prolonged ultraviolet radiation, which causes the proliferation of atypical melanocytes along the dermal-epidermal junction and alters genes in the MAPK and P13K pathways (Sanchez & Grichnik, 2014; Weyers et al., 1996). Within these two pathways, LM is more likely to have mutations in KIT, a proto-oncogene, which is not commonly seen in other subtypes of melanomas (Xiong et al., 2022). Secondary mutations in CCND1, CDKN2A, or p53 result in the transformation of LM into a malignant tumor by allowing unregulated cell proliferation (Bastian et al., 2014).

CLINICAL FEATURES

LM will typically present as an atypical brown macule or patch on sun-exposed areas, typically favoring the cheeks (Figure 1; Cox et al., 1998). Lesions may also appear asymmetric with poorly defined borders (Xiong et al., 2022). LM can mimic benign diagnoses such as solar lentigo, seborrheic keratosis, pigmented actinic keratosis, or even benign nevus (Kasprzak & Xu, 2015), necessitating additional tools to aid in making the diagnosis of LM when viewing suspicious lesions. A few noninvasive tools that can be used to aid in making the diagnosis of LM include dermoscopy, Wood's lamp examination, and reflectance confocal microscopy (RCM).

FIGURE 1. A lentigo melanoma on the lower left cheek in an elderly woman. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

DERMOSCOPY OF LM

Dermoscopy utilizes a handheld conventional or polarized light source to examine dermatologic lesions with 10x magnification and can help distinguish LM from other conditions (Kasprzak & Xu, 2015). Key features of LM that can be identified under dermatoscope include dark rhomboidal structures, gray globules, annular-granular pattern, blue-gray dots, asymmetrical pigmented follicular openings, and black blotches (Figure 2; Iznardo et al., 2020). The presence of a pigmented network may be indicative of melanoma.

FIGURE 2. Dermoscopy of lentigo maligna (LM). In this image, the presence of a reticular granular pattern (green arrows) and asymmetrical pigmented follicular openings (blue arrows) characteristic of LM can be seen. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

WOOD'S LAMP EXAMINATION

Suspicious lesions with an increased concentration of epidermal melanin will appear darker and fluoresce under a Wood's lamp. Moreover, Wood's lamp examination can be a useful tool to identify true margins of LM that cannot be seen with visible light (Kasprzak & Xu, 2015).

REFLECTANCE CONFOCAL MICROSCOPY

RCM is an imaging modality that allows for imaging of live, intact tissue sections obtained with a 100x microscope objective without the need for biopsy of a tissue sample (Rajadhyaksha et al., 1995). The two major criteria for diagnosis of LM under RCM are nonedged papillae and round pagetoid cells > 20 [mu]m (Guitera et al., 2010). Although RCM can serve as a useful tool to facilitate the diagnosis of LM, biopsy and histological examination remain to be the gold standard for the diagnosis of LM.

HISTOPATHOLOGY

Histologically, LM is characterized by atypical melanocytic hyperplasia at the dermoepidermal junction, confluence of atypical melanocytes with angulated, enlarged, hyperchromatic nuclei replacing the basal cell layer, in addition to nesting of atypical melanocytes with potential pagetoid spread (Kasprzak & Xu, 2015). It should be noted that chronic sun damage can also stimulate melanocytic hyperplasia, which is why biopsies from sun-damaged areas of the skin should be taken, if possible, for comparison (McGuire et al., 2012). Furthermore, LM cells often display cytoplasmic retraction and periadnexal extension (Xiong et al., 2022). As LM progresses to LMM, junctional nests become more spindled with invasion. Desmoplasia and perineural invasion may be seen as well (Xiong et al., 2022).

DIFFERENTIAL DIAGNOSIS

As discussed earlier, LM can grossly mimic benign diagnoses such as solar lentigo, seborrheic keratosis, pigmented actinic keratosis, or even benign nevus (Figure 3; Kasprzak & Xu, 2015). Furthermore, under histological examination, LM can also mimic benign melanocytic hyperplasia secondary to chronic sun damage (McGuire et al., 2012).

FIGURE 3. In this image of lentigo maligna on the lower left mandible, one can see how this neoplasm may closely mimic other benign conditions such as a solar lentigo, thus stressing the importance of further examination. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

TREATMENT

The treatment options for LM primarily revolve around whether the patient is a good surgical candidate, as surgical excision is the treatment of choice for LM (Xiong et al., 2022). Numerous studies have reported that traditional 0.5-cm surgical margins for removal of LM are inadequate, with almost half of tumors requiring larger margins for clearance and recurrence rates between 8% and 20% (McGuire et al., 2012; Osborne & Hutchinson, 2002). A 2019 study that treated over 1,500 cases of LM with Mohs micrographic surgery (MMS) showed that 1.2-cm margins were needed for a 97% clearance rate (Kunishige et al., 2019).

There is controversy regarding the preference for MMS versus wide local excision (WLE) for the treatment of LM. Whereas MMS utilizes progressive radial sectioning to examine lesions on frozen-section histology, WLE does not utilize live histological processing and instead removes a fixed margin of tissue (Davis, 2020). The main concern of critics against the use of MMS for LM relates to the potential for residual disease in tumors without contiguous growth patterns (Beaulieu et al., 2018). However, in cosmetically sensitive areas such as the head and neck, MMS may be preferable because of its narrow margins and histological assessment to assess clearance (Davis, 2020). However, there have been multiple studies reporting lower recurrence rates of 1.8%-1.9% in patients with LM treated with MMS compared with recurrence rates of 5.8%-5.9% in patients with LM treated with WLE (Nosrati et al., 2017; Hou et al., 2015). Ergo, preference for surgical modality should be made at the physician's discretion and location of the lesion.

For patients who are not good surgical candidates or wish to avoid surgery, nonsurgical treatments include 5% topical imiquimod and radiation therapy (Kasprzak & Xu, 2015). Topical 5% imiquimod, an immune response modifier, has been used off-label for the treatment of LM. However, the reported efficacy is mixed with clinical clearance rates ranging from 46% to 78% (Marsden et al., 2017). Radiation therapy commonly entails delivering fractionated superficial radiotherapy, or Grenz rays, for the treatment of LM and has documented recurrence rates ranging from 0% to 31% (Hendrickx et al., 2020).

FOLLOW-UP/PROGNOSIS

With complete excision, the prognosis for both LM and LMM is great (Xiong et al., 2022). However, if the tumor is left untreated and becomes invasive, it has the potential to metastasize and drastically reduce 5-year survival rates to as low as 26.1% (Wang et al., 2016). This necessitates accurate diagnosis, via biopsy, and successful treatment of LM.

SUMMARY

LM is a melanocytic neoplasm caused by chronic sun damage that has the potential to progress to LMM if left untreated or misdiagnosed as a benign dermatologic condition. With adequate diagnosis and treatment, the prognosis of LM/LMM is excellent. Therefore, clinicians must be able to differentiate LM from similar dermatologic conditions.

REFERENCES