Section 7. Disorders of Melanocytes

Acquired melanocytic nevocellular nevi are small (<1.0 cm), benign, well-circumscribed, pigmented lesions comprised groups of melanocytes or melanocytic nevus cells.

They can be classified into three groups:

• 1. Junctional nevi (cells grouped at the dermal–epidermal junction, above basement membrane).
• 2. Dermal nevi (cells grouped in the dermis).
• 3. Compound nevi (combination of histologic features of junctional and dermal).

But there is clinical overlap among all three types.

Insight

Only some 30% of melanomas arise from preexisting nevi; thus prophylactically removing all the nevi on a person is neither warranted nor protective.

Synonym Pigmented nevi, nevocellular nevus.

Epidemiology

Age Nevi appear after 6 to 12 months of age, peak during the third decade, and then slowly disappear.

Incidence Common, by age 25, most Caucasians will have 20 to 40 moles.

Gender M = F.

Race Caucasians have more total body nevi than darker skin types. But Asians and blacks have more nevi on atypical locations (palms, soles, nail beds, and conjunctivae) than whites.

Genetics Increased number of nevi tend to cluster in families. Increased clinically atypical nevi may be more prevalent in families with melanoma.

History

Duration of Lesions Commonly called moles, lesions appear after age 6 to 12 months and reach a maximum number between ages 20 and 29. By age 60, most moles fade and/or disappear.

Skin Symptoms Nevocellular nevi are asymptomatic. If a mole is symptomatic, it should be evaluated and/or removed.

Differential Diagnosis

Melanocytic nevi need to be differentiated from seborrheic keratoses, dermatofibromas, neurofibromas, fibroepithelial polyps, basal cell carcinomas, and melanomas.

Management

Indications for removal of acquired melanocytic nevi are:

1. 1. Asymmetry in shape. One-half is different from the other.

   2. Border. Irregular borders are present.

   3. Color. Color is or becomes variegated. Shades of gray, black, white are worrisome.

   4. Diameter. Greater than 6 mm (may be congenital mole, but should be evaluated).

   5. Symptoms. Lesion begins to persistently itch, hurt, or bleed.

   6. Site. If lesion is repeatedly traumatized in any given location (e.g., waistline, neck) or if lesion is in a high-risk/difficult-to-monitor site such as the mucous membranes or anogenital area, it may warrant removal.

These criteria are based on anatomic sites at risk for change of acquired nevi to malignant melanoma or on changes in individual lesions (color, border) that indicate the development of a focus of cells with dysplasia, the precursor of malignant melanoma. Dysplastic nevi are usually >6 mm, and darker, with a variegation of color (tan, brown), and irregular borders. Approximately one-third of melanomas are associated with precursor nevi, and an increased number of nevi increases the melanoma risk.

Melanocytic nevi, if treated, should always be excised for histologic diagnosis and for definitive treatment. Destruction by electrocautery, laser, or other means is not recommended.

Junctional Nevus

Physical Examination

Skin Lesions

Type Macule.

Size Less than 1.0 cm.

Color Uniform tan, brown, or dark-brown.

Shape Round or oval with smooth regular borders (Fig. 7-1).

Arrangement Scattered discrete lesions.

Distribution Random.

Sites of Predilection Trunk, upper extremities, face, lower extremities; may be located on palms, soles, and genitalia.

Dermatopathology

Histology In junctional nevi, the cells and/or nest of nevus cells are located in the lower epidermis.

Dermoscopy Uniform pigment network thinning out toward the periphery of the lesion.

Dermal Nevus

Synonym Intradermal nevus.

Physical Examination

Skin Lesions

Type Elevated papule, nodule, polypoid, or papillomatous lesion.

Color Skin-colored, tan, or brown.

Shape Round, dome-shaped (Fig. 7-2).

Distribution More common on the face and neck, but can occur on the trunk or extremities.

Other Features Coarse hairs may be present within the lesion. Dermal nevi usually appear in late adolescence, 20s, and 30s.

Differential Diagnosis

Dermal nevi are sometimes difficult to distinguish from junctional nevi; and on the face, from basal cell carcinoma.

Dermatopathology

Histology Dermal nevi have nevus cells and/or nests in the dermis.

Dermoscopy Focal globules and white structureless areas.

Compound Nevus

Physical Examination

Skin Lesions

Type Macule or slightly elevated papule, or nodule (Fig. 7-3).

Color Tan, brown, or dark-brown.

Shape Round.

Distribution Any site.

Other Features In late childhood, compound nevi can increase in darkness and become more elevated.

Dermatopathology

Histology In compound nevi, nevus cells and/or nests are seen in both the epidermis and dermis.

Dermoscopy Globular ovoid pattern sometimes in a cobblestone pattern.

Congenital melanocytic nevus (CMN) are pigmented lesions of the skin usually present at birth. CMN may be of any size from very small to very large. CMN are benign neoplasms comprised cells called nevomelanocytes, which are derived from melanoblasts.

Synonym Giant pigmented nevus, congenital nevomelanocytic nevus, garment nevus, bathing-trunk nevus, and giant hairy nevus.

Epidemiology

Age Present at birth (congenital). Rarely, congenital melanocytic nevus become visible after birth (“tardive”), usually within the first 3 to 12 months of life.

Gender M = F.

Race All races.

Incidence Small CMN: 0.5% to 2.5% of the population. Large/giant CMN: 0.005% of the population

Etiology Likely multifactorial. Rare familial cases have been reported.

Pathophysiology

Congenital melanocytic nevi are derived from neural crest-derived melanoblasts embryologically migrating to form the nevus after 10 weeks in utero but before the sixth uterine month. It is unclear what causes these melanoblasts to migrate differently from other melanoblasts when forming the skin

History

Congenital nevi are present at or soon after birth. They begin as pale brown to tan macules, which become darker and more elevated during adolescence. Most of them are benign and grow proportionately with the child and are asymptomatic for life. As the child grows older, the lesions develop coarse terminal hairs and may become more verrucous in appearance.

Physical Examination

Skin Lesions

Type Well-circumscribed macules, slightly raised papules or plaques with or without coarse terminal hairs.

Borders Sharply demarcated, regular contours.

Surface May or may not have altered skin surface (“pebbly,” mammillated, rugose, cerebriform, bulbous, tuberous, or lobular).

Color Light or dark-brown.

Size Small CMN: <1.5 cm; medium CMN: 1.5 to 20 cm (Fig. 7-4A); large/giant CMN: >20 cm (Fig. 7-4B).

Shape Oval or round, symmetric

Distribution Isolated, discrete lesions on any site.

Differential Diagnosis

Without a good birth history, small CMN are often confused with common acquired nevomelanocytic nevi. A CMN can also be confused with a dysplastic nevus, Mongolian spot, nevus of Ota, congenital blue nevus, nevus spilus, Becker’s nevus, neurofibroma, smooth muscle hamartoma, pigmented epidermal nevus, or café au lait macule.

Laboratory Examinations

Histopathology In congenital nevi, the nevomelanocytes occur as well-ordered clusters in the epidermis, and in the dermis as sheets, nests, or cords. Unlike the common acquired nevomelanocytic nevus, the nevomelanocytes in CMN tend to occur in the skin appendages (eccrine ducts, hair follicles, and sebaceous glands) and in nerve fascicles and/or arrectores pilorum muscles, blood vessels (especially veins), and lymphatic vessels, and extend into the lower two-thirds of the reticular dermis and deeper.

Dermoscopy Reticular, globular, reticular-globular, diffuse brown or multicomponent pigment pattern.

Course and Prognosis

By definition CMN appear at birth but varieties of CMN may arise during infancy (so-called tardive CMN). The lifetime risk for development of melanoma in small or medium CMN is low. Patients with large/giant CMN have been estimated to have a lifetime risk of at 4.5% to 6.3% for developing melanoma.

Neurocutaneous melanosis is a rare condition associated with large/giant CMNs, or multiple >3 cm smaller CMNs. Histologically, melanosis may be seen at the base of the brain, ventral surfaces of the pons, medulla, upper cervical, or lumbosacral spinal cord. It may be asymptomatic, or cause seizures, focal neurologic deficits or obstructive hydrocephalus. The latter symptomatic form carries a worse prognosis.

Management

Small (<1.5 cm) and medium (1.5–20 cm) benign-appearing congenital nevi can be safely monitored clinically. Their risk of malignant transformation is too low to warrant removal, thus patients should be instructed about signs of malignant transformation and regular skin examinations should be suffice:

1. 1. Changes in shape. One-half is different from the other.

   2. Irregular or fuzzy borders. Irregular borders are present.

   3. Color variegation. Shades of gray, black, white are worrisome.

   4. Symptoms. Lesion begins to persistently itch, hurt, or bleed.

Large/giant CMN (>20 cm) are clinically difficult to manage since the risk of malignant transformation is present at birth, plus they are logistically more difficult to remove. It is important to follow these lesions clinically with measurements and/or photographs. Complete surgical removal of the lesion is difficult and often requires multiple surgeries with tissue expansion, skin grafting, and/or artificial skin replacement.

An MRI to screen for neurocutaneous melanosis should be considered in neonates with large posterior axial lesions or multiple satellite nevi. Asymptomatic neurocutaneous melanosis can be monitored with repeat scans. Symptomatic neurocutaneous melanosis carries such a poor prognosis that surgical removal of the large CMN is typically not pursued.

Dermabrasion, laser removal, cryosurgery, electrocautery, or curettage of congenital nevi of any size is currently not recommended.

Atypical “dysplastic nevi” are acquired nevi with a clinically atypical appearance: asymmetry, irregular borders, and/or color variation. Histologically, they may exhibit architectural or cytologic atypical cells, the significance of which is controversial.

Synonyms Clark’s nevus, B-K mole.

Epidemiology

Age May appear at any age.

Gender M = F.

Race White 5 black.

Incidence Estimated 5% of the population.

Etiology Familial tendency.

Genetics Autosomal dominant.

Pathophysiology

Genetic loci (1p36 and 9p21) have been implicated in familial cases of dysplastic nevi/ melanoma. Immunosuppression also is associated with an increased risk of dysplastic nevi.

History

Dysplastic nevi typically appear later in childhood (puberty) than benign nevi. They most frequently involve the trunk and show a predilection for covered areas of the body (scalp, breasts in females, and bathing trunk in males), and are more numerous in sun-exposed areas.

Skin Symptoms Typically asymptomatic. Itching or bleeding may be indicators of malignant change.

Physical Examination

Skin Findings

Type Macules, papules, or poorly circumscribed nodules.

Size 6 to 15 mm.

Color Asymmetrically brown, tan, pink, or variegated.

Shape Round to oval with irregular or angulated borders.

Distribution Back > chest > extremities. Predilection for covered areas (scalp, breasts in females, and bathing trunk in males).

Differential Diagnosis

Dysplastic nevi can be confused with acquired nevomelanocytic nevi, small congenital nevi, melanoma, Spitz nevi, seborrheic keratoses, solar lentigines, and other pigmented lesions.

Laboratory Examinations

Dermatopathology The histologic criteria for a dysplastic nevus include the following:

1. 1. Architectural disorder with asymmetry of the lesion.

   2. Intraepidermal melanocytes in a single file or in nests beyond the dermal component.

   3. Lentiginous hyperplasia with elongation of the rete ridges (may be “bridging”).

   4. ± Fibrotic changes around the rete ridges.

   5. ± Vascular changes.

   6. ± Inflammation.

Course and Prognosis

Clinically, it seems atypical nevi are an intermediate on the continuum between normal common nevi and melanoma. The majority of atypical nevi are clinically stable and not inevitable precursors to melanoma. A rare few do progress to melanoma, especially in patients with numerous atypical nevi (see Fig. 7-5) or a positive family history. Thus these patients should self-check for changes in their moles and routinely have their skin checked by a physician.

Management

Patients with atypical nevi should have regular skin examinations with excision and histologic evaluation of any changing or worrisome lesions. These patients should also be educated and instructed on worrisome signs in moles:

1. 1. Asymmetry in shape. One-half is different from the other.

   2. Border. Irregular borders are present.

   3. Color. Color is or becomes variegated. Shades of gray, black, white are worrisome.

   4. Diameter. Greater than 6 mm (may be congenital mole, but should be evaluated).

   5. Symptoms. Lesion begins to persistently itch, hurt, or bleed. If a skin lesion is constantly traumatized in any given location (e.g., waistline, neck) or if lesion is in a high risk/difficult-to-monitor site such as the mucous membranes or anogenital area, it may warrant removal.

It may be harder for patients to follow these general guidelines given the atypical presentation of their dysplastic nevi at baseline, thus routine skin examinations (± photos) with a physician is recommended. Physicians will be looking for lesions that “stand out” or differ from the patient’s other baseline nevi. It is not recommended to remove all clinically atypical nevi, rather close follow-up and removal of changing or worrisome nevi is indicated. Additionally, first-degree relatives of patients with melanoma or atypical nevi should have regular skin checks, and counseling regarding sun avoidance and protection.

A blue nevus is an acquired, benign, small, dark-blue to blue–black, sharply defined papule or nodule of melanin-producing dermal melanocytes.

Synonyms Blue neuronevus, dermal melanocytoma, common blue nevus, blue nevus of Jadassohn-Tieche.

Epidemiology

Age May appear at any age; 18% are present at birth.

Gender F > M, 2:1.

Rare Variants Cellular blue nevus, combined blue nevus-nevomelanocytic nevus, plaque-type blue nevi.

Pathophysiology

A blue nevus arises from ectopic dermal melanocytes. It is thought that melanocytes migrate away from the dermis during the second half of embryogenesis, and that blue nevi represent arrested embryonal migration of the melanocytes. They appear blue because of the Tyndall phenomenon refracting light from the deeper location of the nevus cells.

History

Blue nevi are benign growths that appear during childhood and adolescence, remain stable in size, and persist for life. In contrast, cellular blue nevi are generally >1 cm in size and have a low but distinct danger of malignant transformation.

Physical Examination

Skin Lesions

Type Macule or dome-shaped papule.

Size 2 to 10 mm.

Color Blue, blue–gray, blue–black (Fig. 7-6). Occasionally has target-like pattern of pigmentation.

Shape Usually round to oval.

Distribution Dorsa of the hands and feet (50%), scalp or the face (34%), or buttocks (6%).

Differential Diagnosis

The diagnosis of a blue nevus is usually made on clinical findings. Although worrisome in color, blue nevi can be diagnosed by their normal skin markings. At times, the diagnosis is confirmed by excision and histologic examination. The differential diagnosis includes a radiation tattoo, traumatic tattoo (e.g., pencil lead tip), dermatofibroma, glomus tumor, primary or metastatic melanoma, venous lake, angiokeratoma, sclerosing hemangioma, apocrine hidrocystoma, and a pigmented spindle cell (Spitz) nevus.

Dermatopathology

Histology Skin biopsy reveals spindle-shaped melanocytes grouped in bundles in the middle and lower third of the dermis.

Dermoscopy Homogenous blue–gray or blue–black pigmentation.

Course and Prognosis

Common blue nevi appear and persist throughout life. They may flatten and fade in color over time. Malignant degeneration is rare.

Management

Common blue nevi smaller than 10 mm in diameter and stable for many years usually do not need excision. Those larger than 10 mm are more likely to be the cellular blue nevus variant, which does have a low risk of malignant degeneration, and surgical removal is recommended. The sudden appearance or change of an apparent blue nevus also warrants surgical excision.

A halo nevus is a nevus (usually compound or dermal nevus) that becomes surrounded by a halo of depigmentation. The nevus then typically undergoes spontaneous involution and regression followed by repigmentation of the depigmented area.

Synonyms Sutton’s nevus, leukoderma acquisitum centrifugum, perinevoid vitiligo.

Epidemiology

Age Typically in patients <20 years. Age range: 3 to 42 years.

Gender M = F.

Incidence <1% of patients <20 years.

Family History Halo nevi occur in siblings and in persons with a family history of vitiligo.

Associated Disorders 20% of patients with halo nevi have vitiligo. Most of them also have dysplastic nevi.

Halo Depigmentation Around Other Lesions Typically halo nevi are compound or dermal nevi at the outset. However, halos have also been reported with blue nevi, congenital nevi, Spitz nevi, and melanomas.

Pathophysiology

The triggering mechanism for halo nevi is unclear. It is thought perhaps a halo nevus represents a cell mediated and/or humoral autoimmune response against nonspecifically altered nevomelanocytes. This results in cross-reactivity to distant nevomelanocytes (supported by the clinical observation that 20% of patients with halo nevi also exhibit vitiligo).

History

Three Stages

1. 1. Development (in months) of halo around preexisting nevus.

   2. Disappearance (months to years) of nevus.

   3. Repigmentation (months to years) of halo.

Physical Examination

Skin Lesions

Type Nevus: papular. Halo: macular.

Size Nevus: 3 to 10 mm. Halo:1 to 5 mm beyond the nevus periphery (Fig. 7-7).

Shape Round to oval.

Color Nevus: pink, brown. Halo: initial erythema followed by depigmented white.

Number 25% to 50% of patients have two or more halo nevi.

Arrangement Scattered discrete lesions (1–90).

Distribution Trunk (especially the back).

Laboratory Examinations

Dermatopathology Dermal or compound nevus surrounded by lymphocytic infiltrate (lymphocytes and histiocytes) around and between nevus cells. In the halo areas, there is a decrease or absence of melanin and melanocytes (as shown by electron microscopy).

Dermoscopy Symmetric, white structureless area surrounding the nevus.

Differential Diagnosis

Halo nevi are clinically distinctive, and characterized by a non worrisome junctional, dermal, or compound central nevus. In rare instances, halos of depigmentation can be seen around congenital nevi, atypical nevi, blue nevi, Spitz nevi, primary or metastatic melanoma, dermatofibromas, warts, or molluscum.

Course and Prognosis

The majority of halo lesions undergo spontaneous resolution, with subsequent clearing of the depigmented areas. In a few cases, the halo nevi persist or the nevus regresses, yet the depigmentation persists. Finally, in very rare instances (in adults), multiple halo nevi may be a precursor or sign of melanoma.

Management

Halo lesions undergo spontaneous resolution and the central regressing nevus need not be removed. But the central nevus and complete skin should routinely be evaluated for clinical criteria of malignancy (variegation of pigment and irregular borders) as a halo can rarely be associated with melanoma (ocular or cutaneous). Worrisome or atypical lesions should be excised and sent for histologic evaluation.

A nevus spilus is a flat brown macule dotted with superimposed smaller dark brown-to-black nevi (junctional nevi, compound nevi, Spitz nevi, blue nevi) that develop over time.

Synonyms Speckled lentiginous nevus, spotty nevus, spotted grouped pigmented nevus, nevus-on-nevus, zosteriform lentiginous nevus.

Epidemiology

Age Macular component usually present at birth, but can appear later in life.

Incidence Present in 1.7/1000 newborns, found in 2% of the adult population.

Gender M = F.

Pathophysiology

The pathogenesis of a nevus spilus is unclear, but may represent a localized change in neural crest melanoblasts leading to the simultaneous or subsequent development of multiple different types of nevi. Genetic and environmental factors may play a role.

History

The macular component of a nevus spilus is usually present at birth, but can be acquired. Gradually more and more nevi appear superimposed on the congenital macule giving the nevus a “speckled” appearance. The entire lesion is typically asymptomatic and persists for life, growing proportionately with the child. Rarely, the nevi within the nevus spilus can become atypical.

Physical Examination

Skin Findings

Type Background: macular. Superimposed nevi: small macules or papules (Fig. 7-8).

Color Background: light-brown. Superimposed nevi: brown, blue, or dark brown–black.

Size and Shape Background: 1 to 20 cm. Superimposed nevi: 1 to 6 mm.

Sites of predilection Torso and extremities.

Differential Diagnosis

A nevus spilus can be confused with a café au lait macule, Becker’s nevus, compound nevus, congenital nevus, and/or junctional nevus.

Laboratory Examinations

Dermatopathology Background: epidermal hyperpigmentation with macromelanosomes or lentiginous melanocytic hyperplasia. Superimposed nevi: histologic changes of a congenital, junctional, compound, blue, Spitz, or atypical nevus.

Differential Diagnosis

A nevus spilus can be confused with agminated nevi (the latter has no background lesion).

Course and Prognosis

Nevus spilus rarely develop into malignant melanoma, and often persist throughout life asymptomatic and unchanging.

Management

Because nevus spilus does have nevus areas within it, its nevi should be monitored clinically for signs of worrisome changes, which include the following:

1. 1. Asymmetry in shape. One-half is different from the other.

   2. Border. Irregular borders are present.

   3. Color. Color is or becomes variegated. Shades of gray, black, white are worrisome.

   4. Symptoms. Lesion begins to persistently itch, hurt, or bleed.

The lesions tend to be several centimeters in diameter, thus prophylactic surgical excision is not recommended nor warranted. Routine clinical examination with biopsies and histologic evaluation of any worrisome central nevi is the current recommended approach.

A Spitz nevus is a benign small red–brown, dome-shaped nodule that appears suddenly (typically on the face) of a child. Despite the benign course of the lesion, the histology is misleadingly worrisome, with spindle and epitheloid cells, some of which are atypical in appearance, resembling a melanoma.

Insight

An experienced dermatopathologist is critical when evaluating Spitz nevi since histologically they can look very worrisome and be mistaken for melanoma with dire consequences for the child.

Synonyms Spitz tumor, benign juvenile melanoma, epitheloid cell–spindle cell nevus, Spitz juvenile melanoma.

Epidemiology

Age Appears between ages 3 and 13 years. Rarely seen at birth. Rare in persons >40 years.

Gender M = F.

Incidence 1.4:100000 in Australia.

Pathophysiology

The pathogenesis of a Spitz nevus is unclear. The increased incidence in children, during pregnancy and puberty suggests developmental and hormonal influence.

History

Spitz nevi typically appear suddenly, rapidly grow, and then plateau. They can remain stable for years. They are typically asymptomatic and may persist for life or develop into a dermal nevus.

Physical Examination

Skin Findings

Type Papule or nodule.

Color Pink, tan to red–brown color (Fig. 7-9).

Size 2 mm to 2 cm (average diameter: 8 mm)

Shape Round, dome-shaped.

Distribution 42% found on the head and neck of children/adolescents.

Diagnosis and Differential Diagnosis

The diagnosis of a Spitz nevus is usually made clinically. The differential diagnosis includes a dermal nevus, pyogenic granuloma, hemangioma, molluscum, dermatofibroma, mastocytoma, juvenile xanthogranuloma, and nodular melanoma.

Laboratory Examinations

Dermatopathology Skin biopsy shows large nests of epitheloid and spindle cells with abundant cytoplasm and occasional mitotic figures. The nests extend into the dermis in a characteristic “raining down” pattern. There are also coalescent eosinophilic globules (Kamino bodies) present in the basal layer in 80% of biopsies.

Course and Prognosis

Spitz nevi appear suddenly and enlarge rapidly. They then plateau and persist for years, some may morphologically change into a dermal nevus. Spitz nevi are benign but there are case reports of “metastatic Spitz nevi” in which nevus cells are found in local lymph nodes (the significance of which is unclear) and rare instances of Spitz progression to melanoma.

Management

Because Spitz nevi are benign, in cases with a classic appearance and clinical history, no treatment is needed. However, the rapid onset and growth of the lesion is often worrisome to clinicians and the lesions are often removed by excisional biopsy. Once excised, good dermatopathologic examination is needed to distinguish the Spitz nevi from melanoma. And several consultative opinions may be necessary to rule out melanoma in borderline or atypical Spitz lesions.

Ephelides

Ephelides (freckles) are light-brown macules that occur on sun-exposed skin most frequently observed in light-skinned individuals.

Synonym Freckles.

Epidemiology

Age Not present at birth. Usually appear before age 3 with sun exposure.

Gender M = F.

Season Increase in size, number, and degree of pigmentation during summer. Decrease in winter.

Etiology Related to sun exposure. Maybe autosomal dominantly inherited. Linked with light skin color and red or blond hair.

Pathophysiology

Sun exposure stimulates the melanocytes to focally produce more melanin, and the more fully melanized melanosomes are transported from the melanocytes to the keratinocytes.

Physical Examination

Skin Findings

Type 1- to 5-mm macules.

Color Light-brown to brown.

Shape Round to stellate.

Distribution Sun-exposed skin: nose, cheeks (Fig. 7-10), chest, shoulders, arms, and upper back.

Laboratory Examinations

Dermatopathology Normal number of melanocytes but increased melanin content in the basal keratinocytes.

Wood’s Lamp May accentuate and reveal more freckling.

Differential Diagnosis

The diagnosis of ephelides is made clinically. Ephelides (freckles) differ from lentigines in that ephelides are only in sun-exposed areas and eventually fade with time, whereas lentigines can be found on any site and persist despite sun avoidance.

Course and Prognosis

Mild sun-induced ephelides are benign (unless associated with XP) and tend to disappear with age. Severe sunburn-induced freckles (from a blistering sunburn) are typically more stellate in shape and permanent. When extensive ephelides are seen in persons with dark hair, xeroderma pigmentosum (XP) or a heterozygous carrier for XP should be considered.

Management

Ephelides are benign, fade with time, and do not require treatment. However, they are a marker for increased sun susceptibility coupled with past UV damage. Thus freckled individuals should have regular skin examinations and be counseled regarding avoidance of sun exposure and good sunscreen application.

Cosmetically, ephelides can be masked by cover-up makeup, and eventually lighten with time and sun avoidance. For faster results, ephelides can be lightened with α-hydroxy, salicylic, azeleic acid, hydroquinone, tretinoin, liquid nitrogen, or laser. Care must be taken in these approaches not to worsen the cosmetic outcome with subsequent dyspigmentation.

Lentigo Simplex and Lentigines-Associated Syndromes

A lentigo simplex is a well-circumscribed brown macular lesion with increased numbers of melanocytes (which distinguishes them from ephelides) without any predilection for sun-exposed areas (differing from adult solar lentigines). There are also several syndromes characterized by lentiginosis (Table 7-1).

Epidemiology

Age Can be at or near birth, increase during adolescence, and persist for life. May also be a marker for a lentiginosis syndrome (see Table 7-1).

Gender M = F.

Race All equally.

Pathophysiology

An increased number of melanocytes produce more melanin resulting in hyperpigmented macules. The cause is unknown, but may be from a genetic alteration of the neuroectoderm.

Physical Examination

Skin Findings

Type Macules to patches (Fig. 7-11).

Size <5 mm.

Color Tan, light-brown, dark-brown, or black.

Shape Round or oval.

Number Maybe solitary or numerous.

Distribution Can be found on any cutaneous surface including palms, soles, and mucous membranes.

Differential Diagnosis

The diagnosis of lentigines is made by clinical examination. Lentigines can be difficult to distinguish from ephelides, junctional nevi, solar lentigines, or macular seborrheic keratoses. Lentigines differ from ephelides (freckles) in that ephelides can eventually fade, lentigines persist for life.

Laboratory Examinations

Dermatopathology Increased number of melanocytes along the dermal–epidermal junction and elongation of the rete ridges.

Electron Microscopy Melanin macroglobules found in the of melanocytes, keratinocytes, and melanophages.

Wood’s Lamp May accentuate and reveal more lentigines.

Dermoscopy Light-brown structureless or reticular pattern.

Course and Prognosis

Lentigines, as an isolated finding, are benign and asymptomatic. Typically, the pigmented macules are present at or near birth, increase in number during puberty, persist for life but may fade slightly in adulthood. Their presence may be a marker of a more systemic lentiginosis syndrome.

Management

Lentigines are benign and do not require treatment.

Cosmetically, lentigines can be masked by cover-up makeup, and eventually lighten with time. For faster results, lentigines can be lightened with α-hydroxy, salicylic, azeleic acid, hydroquinone, tretinoin, liquid nitrogen, or laser. Care must be taken in these approaches not to worsen the cosmetic outcome with subsequent dyspigmentation.

Lesions on acral skin or mucous membranes should be monitored for clinical atypia because they can rarely progress to lentigo maligna. Although commonly restricted to the cutaneous surface only, patients with generalized lentiginosis should be monitored for systemic disease.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is a rare autosomal dominantly inherited disorder characterized by familial polyposis and lentigines on the lips and oral mucous membranes. Polyps in the GI tract may occur, with abdominal symptoms manifesting in childhood or early adulthood.

Epidemiology

Age Lentigines appear in infancy and early childhood. GI polyps appear in late childhood, before age 30.

Gender M = F.

Genetics Autosomal dominant with 100% penetrance and variable expressivity; >40% of cases are due to spontaneous mutations.

Etiology Mutation in the STK11 gene.

History

The lentigines can be congenital or may develop during infancy and early childhood. The pigmented macules may disappear over time on the lips, but the pigmentation of the mouth does not disappear and is therefore the sine qua non for the diagnosis. The lentigines occur in some patients who never have abdominal symptoms.

Systems Review Abdominal pain can present anytime between ages 10 and 30. GI bleeding, melena, hematemesis, and anemia may also occur. The small bowel is most often affected, but large bowel, stomach, and esophageal polyps may also occur.

Physical Examination

Skin Findings

Type Macule.

Color Dark-brown or black.

Size 2 to 5.0 mm. Lentigines on the face are smaller than those on the palms and soles and in the mouth.

Shape of Individual Lesion Round or oval.

Arrangement of Multiple Lesions Closely set clusters of lesions.

Distribution of Lesions Intraoral lentigines are the sine qua non of Peutz-Jeghers syndrome; the lesions are dark-brown, black, or bluish-black. They are irregularly distributed on the gums, buccal mucosa, and hard palate (Fig. 7-12). Lentigines also occur on the lips, around the mouth, nose, palms, soles, hands, and nails.

Nails May have longitudinal melanonychia (pigmented streaks or diffuse involvement of the nail bed).

GI Tract Polyps, which may lead to abdominal pain, GI bleeds, intussusception, and obstruction.

Laboratory Examinations

Dermatopathology On skin biopsy, there is increased melanin in the melanocytes and basal cells.

Electron Microscopy Numerous melanosomes with melanocytes and keratinocytes.

Pathology of GI Polyps Hamartomas, with mixture of glands and smooth muscle.

Hematologic Anemia from blood loss may be present.

Gastroenterology Stool examinations may reveal occult bleeding.

Radiologic Studies Imaging of the GI tract is important in patients with the clinical presentation of multiple lentigines of the type noted earlier.

Differential Diagnosis

In Peutz-Jeghers syndrome the mucosal pigmentation (intraorally) is the constant feature that remains throughout life. The differential diagnosis for mucosal hyperpigmentation includes normal mucosal pigmentation in darker skin types, amalgam tattoos, and staining from zidovudine therapy. The lentigines of Peutz-Jeghers can be differentiated from ephelides by being much darker and occurring in areas not exposed to sunlight (e.g., palms, soles). Also, the lentigines are not widely distributed as in the multiple lentigines syndrome (LEOPARD syndrome); they do not occur on the trunk or extremities, but are localized to the central areas of the face, palms and soles, and dorsa of the hands.

Course and Prognosis

There is a normal life expectancy. Symptomatic GI polyps are the most difficult aspect of this syndrome and may require multiple polypectomies to relieve the symptoms. There is also an increased risk of developing gastrointestinal and pancreatic carcinoma.

Management

Skin Lentigines are benign and do not require treatment. Cosmetically, lentigines can be masked by cover-up makeup, and eventually lighten with time. For faster results, lentigines can be lightened with α-hydroxy, salicylic, azeleic acid, hydroquinone, tretinoin, liquid nitrogen, or laser. Care must be taken in these approaches not to worsen the cosmetic outcome with subsequent dyspigmentation.

Other It is recommended that patients with Peutz-Jeghers syndrome have:

1. 1. Hematocrit checked every 6 months for anemia.

   2. Stool examination annually looking for occult blood.

   3. Routine examinations with a gastroenterologist and appropriate GI studies (for patients >10 years, small bowel follow-through examinations, upper endoscopies, and colonoscopies every 2 years).

   4. Surgical polypectomies for symptomatic or large >1.5 cm) GI polyps.

Multiple Lentigines Syndrome

The multiple lentigines syndrome is a multiorgan genodermatosis commonly referred to by its mnemonic: LEOPARD syndrome. Its principal visible manifestation is generalized lentigines (dark-brown macules).

The seven features in the mnemonic are the following:

• L (lentigines)
• E (EKG abnormalities)
• O (ocular hypertelorism)
• P (pulmonary stenosis)
• A (abnormal genitalia)
• R (retardation of growth or dwarfism)
• D (deafness).

Synonyms Multiple lentigines syndrome, cardiocutaneous syndrome, hypertrophic obstructive cardiomyopathy and lentiginosis, lentiginosis profusa syndrome, progressive cardiomyopathic lentiginosis, Moynahan syndrome, Gorlin syndrome.

Epidemiology

Age Lentigines usually present at birth. Extracutaneous features do not appear until puberty. Mean age of diagnosis: 14 years.

Gender M > F.

Incidence Rare.

Genetics Autosomal dominant inheritance with variable expressivity.

Etiology Mutation in PTPN11 gene

History

The lentigines are often congenital and increase in number, size, and darkness around puberty. They then begin to fade slowly throughout adulthood. Extracutaneous features are usually not manifested until puberty and include pulmonary stenosis, obstructive cardiomyopathy, atrial septal defects, primary pulmonary hypertension, pectus deformities, kyphoscoliosis, hypospadias, cryptorchidism, mental retardation, and sensorineural hearing loss. Cardiac abnormalities result in the greatest morbidity associated with the syndrome.

Physical Examination

Skin Findings

Type Numerous well-demarcated macules.

Size 1 to 5 mm.

Color Tan, brown, or black.

Shape Round or oval.

Distribution Lentigines are concentrated on the face (Fig. 7-13A), neck, and upper trunk (Fig. 7-13B) but may also involve the arms, palms, soles, and genitalia. Mucous membranes are spared.

General Findings

Skeletal Growth retardation (<25th percentile), hypertelorism, pectus deformities, kyphoscoliosis, and winged scapulae.

Cardiopulmonary Includes pulmonary stenosis and conduction defects.

Genitourinary Gonad hypoplasia, renal agenesis.

Neurologic Sensorineural deafness, abnormal EEG, slowed peripheral nerve conduction.

Laboratory Examinations

Dermatopathology There is increased number of melanocytes in the basal layer.

Electron Microscopy Increased number/size of melanosomes in the keratinocytes.

Differential Diagnosis

Other lentiginous syndromes such as Peutz-Jeghers should be considered. The multiple lentigines syndrome typically has facial lentigines with sparing of the mucous membranes, whereas Peutz-Jeghers syndrome has marked intraoral involvement. Other lentigines syndromes and their features are listed in Table 7-1.

Course and Prognosis

The skeletal, cardiac, and endocrine abnormalities are the most problematic. The lentigines are only of cosmetic concern and can get darker, larger, and more numerous with age.

Management

Lentigines are benign and do not require treatment. Cosmetically, lentigines can be masked by cover-up makeup, and eventually lighten with time. For faster results, lentigines can be lightened with α-hydroxy, salicylic, azeleic acid, hydroquinone, tretinoin, liquid nitrogen, or laser. Care must be taken in these approaches not to worsen the cosmetic outcome with subsequent dyspigmentation.

The skeletal, cardiac, and endocrine abnormalities are the most problematic for LEOPARD patients. Although the extracutaneous features are usually not manifested until puberty, LEOPARD patients need to be monitored and managed for pulmonary stenosis, obstructive cardiomyopathy, atrial septal defects, primary pulmonary hypertension, pectus deformities, kyphoscoliosis, hypospadias, cryptorchidism, mental retardation, and sensorineural hearing loss. Cardiac abnormalities result in the greatest morbidity associated with the syndrome.

Cafe Au Lait Macules and Associated Syndromes

Café au lait macules (CALM) are large, round, well-circumscribed, light-brown patches that range in size from 1.0 to 5.0 cm. One to three CALM are seen in 10% to 28% of normal individuals, but more than three CALM may be a marker for several syndromes such as neurofibromatosis (Table 7-2).

Epidemiology

Age Present at birth or soon after. Can increase in size and number with age.

Gender M = F.

Prevalence Present in 10% to 28% of the normal population.

Race Blacks > whites.

Etilogy Unclear.

Pathophysiology

The defect leading to CALM formation has not been identified. CALM hyperpigmentation is caused by increased melanogenesis and subsequent higher melanin content in the keratinocytes.

Physical Examination

Skin Findings

Type Macule to patch.

Size 2 mm to 15 to 20 cm (Fig. 7-14).

Color Light-brown: “coffee with milk.”

Shape Round to oval.

Distribution May occur anywhere on the body except mucous membranes.

Laboratory Examinations

Dermatopathology Increase in basal layer pigmentation with giant pigment granules in both the melanocytes and keratinocytes. Giant macromelanosomes (up to 5 μL in diameter) are usually present.

Wood’s Lamp May accentuate and reveal CALM unapparent to visible light.

Differential Diagnosis

A CALM can be confused with an early nevus spilus, linear nevoid hyperpigmentation, Becker’s nevus, postinflammatory hyperpigmentation, or a phytophotodermatitis.

Course and Prognosis

One to three CALM are common in normal individuals. They appear at or near birth, and grow proportionally with the child and are asymptomatic for life.

More than three CALM in one individual is rare (0.5% of the population) and can be a sign of a neurocutaneous disease such as neurofibromatosis, tuberous sclerosis, Albright’s syndrome (polyostotic fibrous dysplasia), ataxia telangiectasia, Silver’s syndrome, basal cell nevus syndrome, Turner’s syndrome, or Cowden’s disease.

Management

CALM are asymptomatic, benign, and do not require treatment. Cosmetically, CALM can be masked by cover-up makeup, or lightened/ cleared with laser.

Congenital Dermal Melanocytosis (Mongolian Spot)

Lesions of congenital dermal melanocytosis are benign, blue–black large macular lesions characteristically located over the lumbosacral area most commonly seen in Asian, black, and Hispanic populations. They typically self-resolve during childhood.

Epidemiology

Age Present at birth and fades during first 1 to 2 years of life.

Gender M = F.

Race Seen in 90% to 100% of Asian infants, 65% to 95% of black infants, 85% of South American Indian infants, 63% of Indian infants, 46% of Hispanic infants, and <13% of white infants.

Etiology Dermal location of melanocytes results in blue–gray appearance to the skin (Tyndall’s phenomenon).

Pathophysiology

Melanocytes undergo embryonic migration from the neural crest to the epidermis. It is thought that these lesions represent migrational arrest with resultant ectopic melanocytes in the dermis, that appear blue–black from the Tyndall phenomenon (longer wavelength colors: red, orange, and yellow are not reflected, but shorter wavelengths colors: blue and violet are reflected giving these lesions the blue color).

History

Lesions of dermal melanocytosiss develop in utero and are most noticeable at birth. They are asymptomatic, benign, and darker in color until age 1 year, enlarge in size until age 2 years, and then spontaneously disappear by age 10 to 12 years. Only 3% to 4% of these lesions persist for life. No melanomas have been reported to occur.

Physical Examination

Skin Findings

Type Poorly circumscribed macule to patch.

Color Deep brown, slate gray to blue–black.

Size Ranges from 1 cm to extensive areas (85% of cases occupy <5% of the body and only 5% involve >15% of the body surface area).

Number Typically single lesion, rarely multiple.

Distribution Anywhere especially buttock, back, shoulders.

Sites of Predilection Lumbosacral region (Fig. 7-15) > back > rest of body

Differential Diagnosis

Lesions of dermal melanocytosis are sometimes mistaken for ecchymoses, but the areas are nontender. Congenital dermal melanocytosis must also be differentiated from a nevus of Ota, a nevus of Ito, and blue nevus.

Laboratory Examinations

Dermatopathology Elongated spindle-shaped melanocytes are present in the mid- to deep dermis.

Electron microscopy Dermal melanocytes have a preponderance of mature melanosomes.

Management

Treatment is unnecessary because these lesions tend to fade by age 10 to 12 in the majority of individuals. Lesions of congenital dermal melanocytosis persist in only 3% to 4% of the population. Cosmetically, lesions can be covered with makeup or laser lightening of the lesion is possible. Extensive dermal melanocytosis should raise the possibility of phakomatosis pigmentovascularis types II and IV.

Nevus of Ota, Nevus of Ito

The nevus of Ota is a unilateral bluish-gray macular discoloration in the periorbital region (trigeminal nerve, first and second branches). The nevus of Ito is a similar blue–gray discoloration located on the neck and shoulder.

Synonyms Nevus fuscocaeruleus ophthalmomaxillaris, nevus fuscocaeruleus acromiodeltoideus, oculodermal melanocytosis, congenital melanosis bulbi, melanosis bulborum and aberrant dermal melanocytosis, progressive melanosis oculi, persistant berrant dermal melanocytosis, oculomucodermal melanocytosis.

Epidemiology

Age Bimodal age distribution: 50% are present at birth or in the first year of life, 36% appear between the ages of 11 and 20 years.

Gender F > M, 5:1.

Race More prevalent in Asians (75% of cases); less commonly seen in East Indians and blacks; and rarely seen in whites.

Prevalence Primary complaint in 0.4% to 0.8% of outpatient visits in Japan.

Etiology Dermal location of melanocytes results in blue–gray appearance of the skin (Tyndall’s phenomenon).

Pathophysiology

During embryonic development, melanocytes migrate from the neural crest to the epidermis. It is thought that the nevus of Ota and nevus of Ito represent melanocytes that have experienced migrational arrest in the dermis. Some have speculated that there is a hormonal influence as well, accounting for the lesions that appear at puberty and the female predominance. Trauma has also been reported as a triggering mechanism.

The nevi of Ota and Ito appear blue–black from the deep dermal location of the melanocytes and the optical Tyndall’s phenomenon (longer wavelength colors: red, orange, and yellow are not reflected, but shorter wavelengths colors: blue and violet are reflected thus visibly blue–black in color).

History

Nevi of Ota/Ito are sometimes present at birth, or can appear during childhood/puberty. They may increase in intensity and extent during the first year of life. They persist for life. Most nevi of Ota/Ito are benign. There are rare reports of sensorineural deafness and melanoma associated with these lesions.

Physical Examination

Skin Findings

Type Poorly demarcated macules to patches with speckled or mottled appearance.

Color Patchy blue–gray, blue–black.

Size 1 to 10 cm.

DistributionOta: Typically unilateral, periorbital region, can involve ipsilateral sclera (Fig. 7-16). Fifty percent of cases involve the ophthalmic and maxillary branches of the fifth cranial nerve. Rarely, pigmentation can also involve conjunctiva, cornea, retina, lips, palate, pharynx, or nasal mucosa. Ito: Typically unilateral neck/shoulder region in the distribution of the posterior supraclavicular and lateral cutaneous nerves. In <5% of cases, these nevi can be bilateral. Nevi of Ota and Ito may also coexist in the same patient.

General Findings

Most nevi of Ota and Ito are seen as an isolated cutaneous findings; 9% of congenital nevus of Ota is associated with open-angle glaucoma. Other rare associations include cellular blue nevi, nevus flammeus (phakomatosis pigmentavascularis), and malignant melanoma.

Differential Diagnosis

Nevi of Ito and Ota are sometimes mistaken for ecchymoses, but the areas are nontender. Nevi of Ito and Ota must also be differentiated from congenital dermal melanocytosis, blue nevi, melasma, and vascular malformations.

Laboratory Examinations

Dermatopathology Skin biopsy demonstrates increased number of dendritic melanocytes in the mid-to-deep dermis.

Management

Nevi of Ota and Ito do not require treatment. Cosmetically, they can be masked by cover-up makeup. They can also be lightened by laser. Because of their risk of malignancy, these nevi should be followed annually and new subcutaneous nodules should be biopsied for histologic examination. If ocular pigmentation is present, routine ophthalmologic examination (checking for glaucoma and/or ocular melanoma) is recommended.