Benign pigmented skin lesions other than melanocytic nevi (moles)

INTRODUCTION — Benign pigmented skin lesions and melanocytic nevi (moles) are common in children and adolescents. Benign pigmented skin lesions, including lentigines, café-au-lait macules, Becker nevi, and dermal melanocytoses (Mongolian spots, nevus of Ota, and nevus of Ito), will be discussed below. Melanocytic nevi and melanocytic nevi variants are discussed separately. (See "Congenital melanocytic nevi" and "Acquired melanocytic nevi (moles)".)

LENTIGO — Lentigines are benign pigmented macules that result from increased activity of epidermal melanocytes [1]. In contrast to ephelides (freckles) that are often seen in children with lightly pigmented skin and fade in the absence of sun exposure, lentigines are persistent. There are two major types of lentigines: simple lentigo and solar lentigo. The mucosal melanotic macule is a variant of simple lentigo that is located on mucosal surfaces, in particular the lower lip.

Simple lentigo — Simple lentigines often appear during childhood as sharply circumscribed, round-to-oval, uniformly brown or brownish-black macules that are usually <5 mm in diameter. There are typically few lesions, with no predilection for sun-exposed sites. However, multiple lentigines may be seen in a variety of disorders (table 1), and lentigines may increase in number or darken in patients with Addison's disease or other syndromes associated with elevated circulating levels of adrenocorticotropic hormone. (See "Causes of primary adrenal insufficiency in children".)

Mucosal melanotic macule — Mucosal melanotic macules, which most commonly develop on the vermilion portion of the lower lip, have a predilection for White adolescent girls and young women [2,3]. Mucosal melanotic macules may also occur on the oral mucosa and genitalia. Patients present with one or more brown to black macules, sometimes with irregular borders and mottled pigmentation. Genital lesions are occasionally >1 cm in diameter.

Multiple perioral and oral mucosal melanotic macules characterize congenital disorders, such as Peutz-Jeghers and Laugier-Hunziker syndromes. Multiple genital melanotic macules are a feature of Bannayan-Riley-Ruvalcaba syndrome (a type of phosphatase and tensin homolog [PTEN] hamartoma-tumor syndrome) (table 1). (See "Congenital and inherited hyperpigmentation disorders", section on 'Genetic syndromes associated with lentiginosis'.)

Solar lentigo — In contrast to simple lentigines, solar lentigines appear only in sun-exposed areas, particularly in sites of greatest cumulative exposure (eg, the face, dorsal hands, extensor forearms, upper trunk) [4]. Because the incidence of solar lentigines increases with age, they are most often seen in adults. However, solar lentigines can develop in children with lightly pigmented skin who have had significant sun exposure, especially on the shoulders following severe sunburns. Multiple tan to dark brown macules, often with irregular borders, are typically present. The lesions range from a few millimeters to >1 cm in diameter (picture 1).

Children with xeroderma pigmentosum develop numerous solar lentigines at an unusually early age (table 1). (See "Xeroderma pigmentosum".)

Large, jagged solar lentigines are a characteristic finding in patients with type 2 oculocutaneous albinism. (See "Oculocutaneous albinism".)

Differential diagnosis — The major consideration in the clinical differential diagnosis of a simple lentigo is a junctional melanocytic nevus. (See "Acquired melanocytic nevi (moles)", section on 'Common acquired melanocytic nevi'.)

The differential diagnosis of a genital melanotic macule that has irregular borders and abnormal pigmentation may include early acral lentiginous melanoma of the genitalia [5]. Dermoscopic findings of ring-like and parallel, brown streak patterns support a diagnosis of benign mucosal melanotic macule [6,7]. (See "Dermoscopy of mucosal lesions".)

Acral lentiginous melanoma of the genitalia is unusual in children and adolescents. If the diagnosis is unclear and there is no palpable component, a shave biopsy can be performed to make the distinction. (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.)

In children, ephelides are the major consideration in the differential diagnosis of solar lentigines, since both are characterized by multiple pigmented macules in sun-exposed areas. However, ephelides fade in the winter, whereas solar lentigines are present year round [8]. Lentigines also tend to be larger than ephelides. In adults, the differential diagnosis is primarily macular seborrheic keratoses and, occasionally, lentigo maligna.

Some variants of solar lentigines, such as ink-spot lentigines (picture 2) and tanning bed-induced lentigines, have dark pigmentation and a stellate outline that may mimic early melanoma. (See "Melanoma: Clinical features and diagnosis", section on 'Differential diagnosis'.)

Management — Solar lentigines that are of cosmetic concern can be treated with liquid nitrogen cryotherapy, lasers that target melanin (eg, quality-switched [Q-switched] ruby laser, picosecond potassium titanyl phosphate [KTP] laser, picosecond alexandrite laser), or intense pulsed light (broadband light). (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Lentigines'.)

Although solar lentigines themselves have no malignant potential, they represent a sign of photodamage that indicates an increased risk for the development of melanoma and nonmelanoma skin cancers during adulthood. In children and adolescents with solar lentigines, a skin examination should be included in the annual physical examination performed by the primary care provider. If the patient also has atypical or numerous nevi, or a family history of melanoma, then referral to a dermatologist is often warranted. (See "Melanoma: Epidemiology and risk factors" and "Cutaneous squamous cell carcinoma: Epidemiology and risk factors" and "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.)

CAFÉ-AU-LAIT MACULE — Café-au-lait macules (CALM) are flat pigmented lesions that may be present at birth or appear during early childhood, often first becoming noticeable following sun exposure (picture 3A-C). They represent localized areas of increased melanogenesis, the etiology of which is not known except when associated with conditions such as McCune-Albright syndrome (mosaic disorder due to a somatic mutation in the GNAS gene encoding the stimulatory G protein's alpha subunit) or neurofibromatosis type 1 (NF1, results from loss-of-function mutations in the NF1 tumor suppressor gene). Although several studies have shown that a single CALM can be found in 25 to 35 percent of children, <1 percent of children have ≥3 CALM [9]. (See "Congenital and inherited hyperpigmentation disorders", section on 'Genetic syndromes associated with café-au-lait macules'.)

CALM range from a few millimeters to >15 cm in size, and they enlarge in proportion to the growth of the child. Their color varies from tan to dark brown and is usually uniform, although in some cases, perifollicular hypopigmentation or a few darker macules may be apparent within the lesions. In general, the color of CALM is a few shades darker than that of the uninvolved skin [10]. Interestingly, CALM that occur within a Mongolian spot are often surrounded by a halo of normally pigmented skin [11]. (See "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis'.)

In patients with "pigmentary mosaicism" (including the small subset with McCune-Albright syndrome), CALM may have a block-like distribution with midline demarcation and an irregular, jagged outline ("coast of Maine") (picture 4). Some authors refer to this as "segmental pigmentation disorder." (See "Pigmentary mosaicism (hypomelanosis of Ito)".)

In contrast, CALM in patients with NF1 and related conditions classically have a relatively smooth border ("coast of California") (picture 3C). Patients with NF1 also tend to have greater numbers of CALM in a more widespread distribution (with the exception of segmental NF1). These CALM have been referred to as "typical" based on their regular borders and uniform pigmentation. Larger CALM in individuals with NF1 should be palpated to exclude the possibility of an underlying plexiform neurofibroma. Histologic features cannot differentiate among CALM in patients with McCune-Albright syndrome, other forms of "pigmentary mosaicism," and NF1. (See 'Differential diagnosis' below.)

Hyperpigmented patches over the posterior axis are occasionally associated with underlying spinal dysraphism, especially in the presence of additional cutaneous findings such as focal hypertrichosis or a lipoma.

Differential diagnosis — In a neonate, the differential diagnosis of a single CALM includes the initial stage of a speckled lentiginous nevus (ie, before the appearance of superimposed "spots") or a relatively flat congenital melanocytic nevus (which will likely become more elevated over time). Additional diagnostic considerations may include mastocytoma, postinflammatory hyperpigmentation, and phytophotodermatitis.

A Becker nevus should be considered for large, solitary lesions that break up into smaller macules at their periphery (with or without associated hypertrichosis), particularly when located on the upper lateral trunk or when onset occurs around the time of puberty. (See 'Becker nevus' below.)

The key question in the evaluation of a child with multiple CALM is whether these lesions represent a cutaneous marker of an underlying systemic disorder. In a longitudinal study of 41 children with ≥6 CALM, 24 (60 percent) were found to have NF1, 6 had segmental NF1, and 3 were diagnosed with other syndromes (table 1); only eight (20 percent) had no manifestations of an associated condition [12]. In another retrospective study of 110 children (median age three years) who presented with CALM but no other features of NF1, 34 of 44 (77 percent) of those with ≥6 "typical" CALM (distinct regular borders, uniform pigmentation) eventually met criteria for NF1 (almost all before age six years). In contrast, 2 of 15 (15 percent) of those with ≥6 "atypical" CALM (irregular borders, nonhomogeneous pigmentation) and 0 of 51 of those with <6 CALM eventually met criteria for NF1 [13].

The presence of ≥6 CALM (measuring ≥1.5 cm in adults and ≥0.5 cm in prepubertal children) is a criterion for the diagnosis of NF1 that is met by 90 percent of patients by early adulthood. Segmental NF1 (due to mosaicism for a mutation in the NF1 gene) can present with various combinations of multiple CALM, "freckling" (multiple small lentigines), or neurofibromas; the pigmentary abnormalities may have a block-like distribution pattern or follow the lines of Blaschko. In contrast to NF1, multiple CALM are found in a minority of patients with NF2-related schwannomatosis (NF2; bilateral vestibular schwannomas), making their presence less useful in establishing the diagnosis. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)

Legius syndrome, which is secondary to a loss-of-function germline mutation in the SPRED1 gene, has a cutaneous phenotype that partially overlaps with that of NF1 (CALM, freckling) but lacks neurofibromas or Lisch nodules [14]. (See "Congenital and inherited hyperpigmentation disorders", section on 'Neurofibromatosis type 1-like syndrome (Legius syndrome)'.)

Familial CALM, unassociated with other abnormalities, may also occur outside the setting of Legius syndrome [15-17]. Pigmentary disorders that can present with multiple CALM include piebaldism (CALM in leukodermic and uninvolved skin) and familial progressive hyper- and hypopigmentation. Other conditions associated with multiple CALM include Noonan syndrome, Noonan syndrome with multiple lentigines (previously known as LEOPARD [lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness] syndrome), constitutional mismatch repair-deficiency (CMMR-D) syndrome (childhood tumor syndrome with NF1 phenotype), ataxia-telangiectasia, phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome, Russell-Silver syndrome, and Bloom syndrome. (See "Causes of short stature", section on 'Noonan syndrome' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Constitutional mismatch repair-deficiency syndrome' and "Ataxia-telangiectasia" and "PTEN hamartoma tumor syndromes, including Cowden syndrome" and "Causes of short stature", section on 'Silver-Russell syndrome' and "Bloom syndrome".)

Management — If desired for cosmetic reasons, CALM can be treated with pigment-specific lasers, such as the quality-switched (Q-switched) ruby, Q-switched alexandrite, and Q-switched neodymium:yttrium aluminum garnet (Nd:YAG) lasers; nonablative fractional 1550 nm erbium-doped fiber laser; and alexandrite picosecond laser. However, multiple treatment sessions are usually required, responses are variable, recurrences are common, and there is a risk of side effects, such as persistent hyperpigmentation or hypopigmentation. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Cafe-au-lait macules'.)

Infants and young children with ≥6 CALM should be evaluated for other manifestations of NF1 (eg, plexiform neurofibromas, sphenoid or tibial dysplasia, and Lisch nodules) and followed with annual physical examinations that include measurement of blood pressure and examination of the skin and eyes during the first decade of life [18,19]. Referral to a pediatric dermatologist or specialized NF1 clinic can also be considered. Of note, comprehensive testing of the NF1 gene is clinically available and can identify the underlying mutation in ≥95 percent of nonfounder patients who meet the diagnostic criteria for NF1, allowing an accurate diagnosis to be made in young children who do not (yet) meet these criteria. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

BECKER NEVUS — Becker nevus, also called Becker melanosis, is a fairly common benign cutaneous hamartoma with epidermal or dermal elements [18]. Becker nevi can be present at birth, but the majority are first noticed around puberty. This timing of onset, along with the male-to-female ratio of 5:1, the increase in the number of terminal hairs seen within many lesions, and reports of acne vulgaris localized to Becker nevi, has raised the possibility of androgenic stimulation as an underlying factor in their pathogenesis [20]. Evidence suggests that somatic mutations of beta-actin (ACTB) in pilar muscles are associated with Becker nevus [21].

A Becker nevus classically manifests unilaterally on the shoulder and upper trunk as a tan to brown patch or thin plaque. Less often, lesions occur on the lower trunk, thigh, or in other sites. The margins are usually irregular and break up into "islands" at the periphery (picture 5); the average diameter is >10 cm. Hypertrichosis is present in approximately one-half of cases [22], and there can be an associated smooth muscle hamartoma (sometimes evident clinically by perifollicular papules that are accentuated by rubbing). Associated developmental abnormalities, such as hypoplasia of the ipsilateral breast or pectoralis major muscle, occur infrequently.

Differential diagnosis — There are several considerations in the differential diagnosis of Becker nevi:

●Clinically, a Becker nevus can be confused with a congenital melanocytic nevus; however, histologically, Becker nevi are not composed of melanocytic nevus cells. (See "Congenital melanocytic nevi".)

●Smooth muscle hamartomas have significant clinical and histologic overlap with Becker nevi.

●Plexiform neurofibromas, which often have hyperpigmentation and even hypertrichosis of the overlying skin, may be considered in the differential diagnosis of Becker nevi with an associated smooth muscle hamartoma. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Peripheral neurofibromas'.)

●Depending on the location of the lesion and the number of peripheral islands, a Becker nevus without hypertrichosis can be difficult to distinguish from an isolated café-au-lait macule (CALM). (See 'Café-au-lait macule' above.)

Management — Patients with Becker nevi should be examined clinically for associated soft tissue and bony abnormalities. If desired for cosmetic reasons, the hyperpigmented component of Becker nevi can be treated with the quality-switched (Q-switched) ruby laser, the Q-switched neodymium:yttrium aluminum garnet (Nd:YAG) laser, or resurfacing lasers (although responses are variable and recurrence rates are high) and the associated hypertrichosis with laser-assisted hair removal. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Becker's nevus' and "Removal of unwanted hair", section on 'Laser and intense pulsed light'.)

DERMAL MELANOCYTOSES — In normal skin, only melanocytes in the epidermis and hair follicles produce melanin. In dermal melanocytoses, melanocytes in the dermis actively synthesize melanin. The blue color of such skin (ceruloderma) is due to the preferential scattering of shorter wavelengths of light by the dermal melanin, a phenomenon known as the Tyndall effect.

The spectrum of dermal melanocytoses includes:

●Mongolian spots (sacral and extrasacral)

●Nevus of Ota-like macules/acquired dermal melanocytosis (grayish-brown macules in a bilateral, symmetric distribution on the malar cheeks and forehead, seen primarily in middle-aged Eastern Asian women)

●Nevus of Ota

●Nevus of Ito

Nevus of Ito has some overlap with patch-type blue nevi, which represent dermal melanocytomas (ie, a proliferation of melanin-producing dermal melanocytes). (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi'.)

Congenital dermal melanocytosis (Mongolian spots) — Congenital dermal melanocytosis (Mongolian spots) typically appears as congenital blue-gray patches with indefinite borders (picture 6), most often on the sacral area and buttocks in Asian and Black children. They are discussed in detail elsewhere. (See "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis'.)

Nevus of Ota — Nevus of Ota (oculodermal melanocytosis, nevus fuscocaeruleus ophthalmomaxillaris) is a type of dermal melanocytosis that preferentially involves the areas innervated by the first and second divisions of the trigeminal nerve [23]. These lesions differ from Mongolian spots clinically in their mottled, rather than uniform, pigmentation and histologically in their greater density of melanocytes within the upper reticular dermis.

Nevus of Ota occurs most commonly in Eastern Asian and Black individuals. The incidence in Japan, for example, is 1 to 2 per 1000. The female to male ratio is approximately 4:1. Up to 15 percent of lesions harbor somatic activating mutations in the GNAQ and GNA11 genes encoding G protein alpha subunits [24].

The pigmentation is present at birth or within the first year of life in more than one-half of cases, and in the remainder, it becomes apparent around puberty; in both instances, the lesions persist. Patients present with speckled or mottled, grayish-brown to blue-black patches involving the skin, conjunctiva, sclera, tympanic membrane, or oral and nasal mucosa of the affected dermatomes (picture 7). Approximately 10 percent of patients have bilateral involvement. Superimposed elevated areas with the histologic features of blue nevi occasionally develop, and iris mammillations may be seen. (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi'.)

Symptomatic or asymptomatic neurocutaneous melanosis can occur, typically with central nervous system (CNS) involvement ipsilateral to the skin lesions. Approximately 10 percent of patients develop glaucoma, and ipsilateral sensorineural hearing loss has also been described. (See "Congenital melanocytic nevi", section on 'Neurocutaneous melanosis'.)

Melanoma may rarely develop in patients with nevus of Ota, with the uveal tract (ie, the choroid) being the most common primary site, followed by the CNS, orbit, and skin. Although the prevalence of nevus of Ota is higher in Asian patients, the majority of melanoma cases have occurred in White patients, with a mean age at diagnosis of approximately 50 years [25]. In a review of nearly 8000 patients with uveal melanoma, oculodermal melanocytosis was present in 3 percent of the cases [26]. Patients with uveal melanoma and oculodermal melanocytosis had a nearly two-fold increased risk of metastasis compared with those without dermal melanocytosis. (See "Initial management of uveal and conjunctival melanomas".)

Management — Patients with nevus of Ota should be followed with annual ophthalmologic examinations and educated regarding the clinical signs of ocular and cutaneous melanoma (eg, pain or visual changes and a new papule or nodule, respectively). If patients are unable to perform cutaneous self-examinations, they should have longitudinal dermatologic evaluation. (See "Screening for melanoma in adults and adolescents".)

The cutaneous discoloration of nevus of Ota can be treated with the quality-switched (Q-switched) ruby laser, Q-switched alexandrite laser, Q-switched neodymium:yttrium aluminum garnet (Nd:YAG) laser, or alexandrite picosecond laser. This typically requires several sessions, but the outcomes are usually good to excellent [27]. Hypo- or hyperpigmentation are potential side effects. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Nevus of Ota'.)

Nevus of Ito — Nevus of Ito (nevus fuscocaeruleus acromiodeltoideus) is a type of congenital dermal melanocytosis involving areas of skin innervated by the posterior supraclavicular and lateral brachiocutaneous nerves; it is otherwise clinically and histopathologically similar to nevus of Ota.

SUMMARY

●Lentigines – Lentigines are persistent, benign, pigmented macules (usually <5 mm in diameter) that result from increased pigment production from epidermal melanocytes. Multiple lentigines may be seen in a variety of disorders (table 1). Solar lentigines occur only in sun-exposed areas and represent a sign of photodamage that indicates an increased risk for the development of melanoma and nonmelanoma skin cancers during adulthood. (See 'Lentigo' above.)

●Café-au-lait macules – Café-au-lait macules are flat, tan to dark brown pigmented lesions that may be present at birth or appear during early childhood (picture 3A). The presence of ≥6 café-au-lait macules is a criterion for the diagnosis of neurofibromatosis type 1 (NF1). (See 'Café-au-lait macule' above and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

●Becker nevus – Becker nevus is a benign cutaneous hamartoma with epidermal or dermal elements. Most Becker nevi are first noticed around puberty (picture 5), but some are apparent at birth. Considerations in the differential diagnosis of Becker nevus include café-au-lait macule, congenital melanocytic nevus, smooth muscle hamartoma, and plexiform neurofibroma. (See 'Becker nevus' above.)

●Dermal melanocytoses:

•Congenital dermal melanocytosis – Congenital dermal melanocytosis (Mongolian spots) typically appears as congenital, blue-gray, pigmented patches with poorly defined borders (picture 6). (See "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis'.)

•Nevus of Ota – Nevus of Ota primarily involves the areas of skin innervated by the first and second divisions of the trigeminal nerve (picture 7). Potential complications include symptomatic or asymptomatic neurocutaneous melanosis, glaucoma, sensorineural hearing loss, and melanoma. Patients with nevus of Ota should be followed with yearly ophthalmologic examinations and educated regarding the clinical signs of ocular and cutaneous melanoma. (See 'Nevus of Ota' above.)

•Nevus of Ito – Nevus of Ito resembles nevus of Ota clinically and histopathologically but involves the areas of skin innervated by the posterior supraclavicular and lateral brachiocutaneous nerves. (See 'Nevus of Ito' above.)