Anatomy of the Dermis and Epidermis

The skin is a morphologically and functionally complex tissue providing protection against physical elements by its anatomic structure and potential for immune responsiveness. The outermost layer is the stratum corneum or horny layer, which is composed of devitalized keratinocytes (see Fig 71-1). While the dermal layer is a derivative of the paraxial mesoderm, embryologically the epidermis is of ectodermal origin.

The basal layer of the epidermis is the site of mitotic activity leading to the proliferation of keratinocytes. This basal layer consists of columnar cells anchored to the basement membrane via hemidesmosomes and anchored to the dermis via penetrating fibrils (see Fig. 71-1). Interspersed between the basal cells reside melanocytes that are dendritic cells and are the source of melanin (see Fig. 71-2). Melanocytes are not secured via desmosomes or tonofilaments. Functional units (epidermal melanin units) are composed of a melanocyte and the keratinocytes to which it is responsible for the transfer of melanin. Melanosomes are the cytoplasmic organelles that result from the fusion of vesicles containing tyrosinase and vesicles containing the structural melanosomal proteins, both of which are generated by the melanocyte’s endoplasmic reticulum. Differential skin pigmentation amongst individuals results from the variable production of melanosomes, their content and rate of degradation, and not on numbers of melanocytes. The absence of tyrosinase prevents formation of melanosomes and results in albinism. The melanosomes migrate from the perinuclear area along microtubules to the dendritic tips where these are phagocytized by the keratinocyte. As the squamous cells differentiate, the melanosomes are degraded by lysosomal enzymes.

The more superficial layer of dermis is the papillary dermis, which interacts with the epidermis via a basement membrane and sends interdigitating papillary and neurovascular structures to support the epidermis. The appendages to the skin, the hair follicles, sweat, sebaceous and apocrine glands, originate in the dermis. The fibroblast-derived matrix of collagen and elastin reside primarily in the deeper, reticular dermis.

Congenital Nevi

CMN are pigmented lesions of variable size that develop during the first few months of life. They are the consequence of failure of melanocytic migration into the epidermis. These lesions grow proportionally with the infant and are generally categorized as small (<1.5 cm), medium (1.5–20 cm), and large (>20 cm). Those especially large lesions (>40 cm) are also referred to as a garment nevus, giant hairy nevus, or bathing trunk nevus since they tend to cover large truncal areas in confluence (Fig. 71-7). Although the pigmentation and surface are initially uniform and flat, the lesions evolve into thick, dark, and often hair-covered lesions. Histologically, the melanocytic cells in congenital nevi are located deeper than in acquired nevi (Fig. 71-8). The absence of superficial involvement may explain why transformation is often not noticed until late in its development. The incidence of transformation is greatest in the large or giant congenital nevi, and low in small to medium size lesions. The size of the congenital nevus therefore becomes the key element in discussing management.

Excision of small and medium CMN can be delayed or avoided in favor of lifelong observation. The estimated lifetime risk of melanoma in these lesions is estimated at 1%, and most occur after puberty. Biopsy may be of value in stratifying the risk of malignant degeneration. If histological examination shows the more superficial variant, continued observation is warranted, since any transformation is likely to be associated with epidermal changes that will be apparent on close follow-up or self-examination. If the histological variant demonstrates deep melanocytes, then prophylactic excision is recommended.

The management of large or giant CMN is more controversial. The melanoma risk for these lesions is increased and estimated to be 5–10% over a lifetime with 50% of this risk during the first five years of life.3,4 The highest risk lesions are associated with the nevus that is situated over the posterior trunk, greater than 40 cm in maximal dimension, and associated with satellite nevi. Melanoma in these patients can arise from the deep dermal layer or even originate from sites distant from the skin such as the CNS (2.3% in one study⁵) or retroperitoneum.⁴ These patients are also at risk for neurocutaneous melanosis (7% in one study⁵) and CNS malformations such as Dandy–Walker malformation, defects of the vertebra, skull, and intraspinal lipomas. Screening MRI of the brain and spinal cord is recommended during first six months of life in these patients.⁵ Conversely, two-thirds of patients with neurocutaneous melanosis have giant CMN and the others have multiple nongiant lesions. The prognosis for patients with symptomatic neurocutaneous melanosis is extremely poor even in the absence of malignancy.⁶ The increased routine surveillance with MRI during infancy for children with large CMN has identified those with asymptomatic CNS involvement, and hopefully will impact the care and outcome of these patients in a positive manner. These patients are also at risk for other soft tissue malignancies such as rhabdomyosarcoma⁷ or neurofibrosarcoma (peripheral nerve sheath tumor).

Since operative resection of these extensive lesions is often not feasible and never completely eliminates the risk for melanoma, these patients need close medical surveillance. Areas of epidermal change within the nevus should be biopsied. However, caution must be exercised in interpreting the histological results, since the proliferative nodules may resemble melanoma, but behave in a benign manner.⁸ Features useful in differentiating a cellular nodule from melanoma include: (1) lack of high grade uniform cellular atypia; (2) lack of necrosis within the nodule; (3) rarity of mitoses: (4) evidence of maturation; (5) lack of pagetoid spread; and (6) no destructive expansile growth.⁹

When operative intervention is needed, collaboration with colleagues with added expertise in the use of tissue expanders, rotational flaps, and skin grafting may be helpful. In one study, the mean age for intervention was 5.1 years and took an average 1.3 years to complete resection and reconstruction in these patients with large and giant CMN.¹⁰ While the authors expressed a preference for earlier intervention, they acknowledged that the average age of the patients referred to them was 4.7 years, and many had already undergone an operative procedure. Over half of the cohort required more than one operative intervention and 22 of 40 patients needed skin grafts. Also, 18 patients benefitted from tissue expanders and autologous cultured skin replacements.

Acquired Nevi

Acquired nevi are benign neoplasms of the skin which appear after 6 months of age and persist through the fourth decade, after which many disappear. They are most frequently located on sun-exposed areas and are rare on the breast or buttock. Common to all these acquired nevi is that they are less than 6–8 mm in diameter, symmetric in shape, have a homogeneous surface and even pigmentation, and have a regular outline with a sharply demarcated border. On close inspection, they may have some pigmentary stippling.

Histologically, these acquired melanocytic nevi are divided into subtypes based on the location of the nests of nevus cells, and this feature corresponds with certain clinical findings (see Table 71-2). Junctional nevi tend to be flat with brown/black pigmentation and the nevus cells are located at the dermal–epidermal junction. When the nevus cells extend from the junction into the dermis, the lesion is described as a compound nevus. Clinically, this corresponds to a lesion that is slightly raised and pigmented brown/black. When the nevus cells migrate completely into the dermis, the lesion is an intradermal nevus, which is raised and typically not pigmented. In general, the deeper the nests of nevus cells, the more raised and less pigmented the lesion. (i.e., dark flat lesions vs raised tan lesions). The temporal evolutionary path of nevi was originally described by Stegmaier and explains the clinical observations of progressive change within individual nevi or their resolution.¹¹ Newer nevi tend to be small and flat (junctional), and either develop a raised profile or disappear with time as a consequence of fibrosis. In one study, when the nevi on adolescents were followed over a 4-year period, there was a net increase of 50% in total number of nevi, despite a complete regression in 15%.¹² This demonstrates the potential for active turnover in individual patients. Freckling and lighter colored skin are associated with increased numbers of nevi. In darker skinned individuals, nevi also develop, but are usually found on the palms and soles, unlike in the more fair complexioned individuals.

Sun exposure during childhood, especially when it is intense, intermittent, and not necessarily associated with sunburn, is a promoter for nevus development, and is the major environmental factor associated with the risk of melanoma. Recent evidence suggests that sunscreen use has led to a false sense of security in that it provides incomplete protection to UV rays.¹³ Sunscreen alone does not provide sufficient protection. Public health education must focus on the avoidance of midday sun and the use of physical barriers such as UV protectant clothing and hats.^13–16

The role for excision of these acquired nevi is limited when they are clearly defined by their age at presentation and the features described in Table 71-2. The natural evolution and changes in these common lesions should not be mistaken for malignant progression.

Atypical Nevi

Atypical nevi, previously referred to as dysplastic nevi or Clark’s nevi, are common lesions found in 5% of the population, and may occur either sporadically or in a familial pattern (Fig. 71-9). The onset of their first appearance is usually during adolescence on the sun-exposed areas of skin, and they continue to increase in number and size with age. Unlike the common acquired nevi, these lesions are usually larger than 5 mm (up to 15 mm), and have an irregular surface ranging from completely flat to flat with a raised center resembling a fried egg. The pigmentation usually is dark and irregular, and the border of the lesion is often irregular as well. These lesions are most common in persons with light skin and hair color. Ultraviolet light has been implicated in the transformation of melanocytes in these nevi.

When a patient has multiple atypical nevi or moles, they may be diagnosed with the atypical mole syndrome. While it can be normal to have up to 10 to 20 nevi, people with this syndrome may have in excess of 100 moles. Individuals with 50–100 nevi and one or more first- or second-degree relatives with melanoma are considered to have the familial atypical mole and melanoma (FAMM) syndrome that identifies them at significantly increased risk (approaching 100%) for the development of melanoma. It is important to note that the melanoma may arise de novo on any part of the body and not necessarily from a preexisting atypical lesion. Simple excision of an atypical nevus therefore does not obviate the patient from close dermatologic follow-up. In families with the FAMM syndrome, nevi arising on the scalp can be an early predictor for this syndrome, although the scalp nevus itself may involute with time. In these individuals, the nevi tend to be similar in appearance, the corollary being that a new nevus that varies in appearance or location should be regarded with suspicion. The ability of clinical health care providers as well as nonclinicians to identify the ‘ugly duckling’ has been found to be reliable.¹⁷ Routine surveillance examinations with photo documentation are recommended with dermoscopic (epiluminescence microscopy) evaluation of those nevi undergoing significant change. Dermoscopy has been shown to improve sensitivity and specificity with regard to detecting melanoma.¹⁸

Atypical nevi are not necessarily removed to confirm the histological pattern of atypia, but should be biopsied when melanoma is suspected. The biopsy should encompass a 1–2 mm rim of normal tissue and be sufficiently deep to allow to assess the depth of invasion in the event that melanoma is identified. The original designation of dysplastic nevus has been replaced with the term atypical nevus, and the pathologic description currently should use the term ‘nevus with architectural disorder’ and indicate the extent of cytologic atypia. The concordance between clinically atypical nevi and the histological findings of dysplasia is poor. These lesions are at the heart of much of the unfortunate controversy and misinformation that surrounds patients and referring physicians with terms and descriptions of atypia and dysplasia. These descriptive features have led to inappropriate re-excision of some lesions, and have even prompted sentinel lymph node biopsies for a completely benign process. Expert dermatopathologic review is essential for achieving the best care.

Specific Congenital or Acquired Melanocytic Lesions Requiring Distinction from Melanoma

Several melanocytic nevi are discussed separately due to their unique features, which frequently prompt their evaluation for malignancy. These lesions can be congenital or acquired, and are described in terms of their junctional, compound, or dermal location (Table 71-4). A recent review by Schaffer provides some practical advice regarding these specific lesions.¹³

Halo nevi (Sutton’s nevi) are unique lesions which appear between 6–15 years of age, and are typically located on the trunk or extremities. They appear as round or oval lesions, with a central area of pigmentation that may be tan to brown in color, and are surrounded by a rim of depigmentation (Fig. 71-10