Pathology of Benign Melanocytic Nevi

The term benign melanocytic nevus refers to a heterogeneous group of nonmalignant melanocytic nevi manifesting either as pigmented or nonpigmented cutaneous lesions.

The prototypical benign melanocytic nevus is the common acquired nevus, which typically appears within the first 3 decades of life. Characteristically, these are smaller than 6 mm with even pigmentation and smooth borders, commonly found on sun-exposed sites. Common acquired nevi are composed of nevomelanocytic nests and are sometimes classified according the histologic location of the nests (eg, junctional, compound, or intradermal). ^[1]

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In 1893, Paul Gerson Unna, a German dermatologist, presented the concept of Abtropfung, in which melanocytic nevus cells develop in the epidermis, then "drop off" into the dermis over time. ^[2] This hypothesis detailed the sequential development of junctional, compound, and finally purely dermal melanocytic nevi.

It is now established that melanocytic nevus precursor cells are derived from neural crest tissue and migrate to and populate the developing epidermis of the embryo. ^[3] Assuming that all precursors reach their final destination, the epidermis would represent the usual source of melanocytic nevus cells, thus supporting the concept of Abtropfung. ^[4]

Ultraviolet (UV) radiation is an inciting agent in the development of common acquired nevi. However, the required intensity and duration of exposure are less clear. Several studies have suggested an association between sunburns, in particular before the age of 20 years, and larger numbers of nevi as well as the risk of malignant melanoma. ^{[5, 6, 7]} It also appears that chronic UV radiation exposure in children living in sunny climates is sufficient for the development of large numbers of melanocytic nevi. ^[6]

Nevi may also develop on sun-protected sites, and studies regarding the efficacy of sunscreen in preventing nevus development have yielded conflicting results. ^{[8, 9]} These findings suggest that other mechanisms for nevogenesis may exist.

On the cellular level, melanocytic hyperplasia and increased melanin production are common observations in sun-exposed skin. Additionally, UV radiation contributes to direct DNA damage, the formation of reactive oxygen species, and the production of epidermal cytokines, growth factors, and neuropeptides. ^[10] Such alterations in genetic makeup and the cytokine milieu cause impairment of cellular signaling between keratinocytes and melanocytes, which presumably leads to the formation of melanocytic nevi.

Germline and somatic mutations

Studies from families with multiple melanomas and atypical nevi (familial atypical multiple mole–melanoma [FAMMM] syndrome, also known as B-K mole syndrome) have identified germline mutations of the p16 gene (CDKN2A) on chromosome 9p21, which encodes a negative regulator of cell growth. ^[11] In contrast, germline mutations have not been found in subjects with common acquired nevi. Rather, somatic mutations of BRAF (V600E) on chromosome 7q34 have been detected in the majority of these nevi. ^[12]

BRAF is a component of the mitogen-activated protein (MAP) kinase signaling pathway, which is a complex cascade of protein kinases that relays mitogenic signals from the cell surface to the cell nucleus. ^[13] Constitutive kinase activation of the BRAF (V600E) mutation points to a possible role of this intracellular signaling kinase in nevogenesis. ^[4] This possibility is supported by the finding that mutant BRAF was sufficient for nevi formation in animal models. ^[14]

The role of UV radiation in the induction of BRAF mutations is debated. The majority of common acquired nevi, which are associated with UV radiation, harbor this mutation. However, the link is hampered by the fact that BRAF mutations have been detected in congenital nevi and nevi from sun-protected sites. ^[15] Additionally, BRAF mutations have been detected in colorectal carcinomas and papillary thyroid carcinomas, which suggests that additional pathways for BRAF mutagenesis may exist.

Factors influencing nevus density

Race, sex and UV radiation have been shown to influence nevus density. In studies from children and adolescents, nevus counts are higher in chronically sun-exposed areas (arms or face and neck) than in intermittently exposed areas (back, chest, or legs). ^[16] For males, nevi are concentrated on the face and neck, compared with the upper lateral arms and thighs in females. ^[16]

Interestingly, a higher proportion of larger (>5 mm) nevi are located on the back. ^[17] This observation has led authors to suggest that there may be site-specific differences in the stability of nevi, ^[18] that there may be an effect of nonhabitual UV exposure, ^[19] or both.

Common acquired nevi are not limited to hair-bearing skin: they can be seen in volar skin, beneath fingernails and toenails, and within the conjunctivae and uveal tracts. ^[20] Dark-skinned individuals have lower total body nevus counts than light-skinned individuals. ^[21] Individuals with darkly pigmented skin tend to develop nevi on the palms and soles (acral nevi). ^[21] When acral nevi involve the nail matrix, they can present as a black streak within the nail plate (longitudinal melanonychia).

An average white person has 15-40 common acquired nevi over a lifetime. ^[20] Nevi counts peak in the third decade of life and diminish with increasing age. ^[20]

Constitutional factors have been shown to define the predisposition and pattern of nevus development. ^[4] Total nevus counts are higher in males than in females across the age continuum. ^{[5, 22, 23]} Independent of sun exposure, girls generally have more nevi on the limbs, whereas boys have more nevi on the trunk. ^{[17, 24]}

Nevus counts in children correlate with the number of parental nevi, ^[25] and the correlation of nevus counts is higher amongst monozygotic twins. ^[26] It is also observed that females with Turner syndrome (45, XO) have a higher incidence of common acquired nevi. ^[4]

Additionally, numerous studies suggest a correlation between pigmentary traits and nevus counts. Children with light skin, blond or red hair, gray or blue eyes, freckling, and a propensity to burn rather than tan have significantly higher nevus counts than children without these characteristics. ^{[6, 25]}

A debated exception to this generalization would be that children with red hair or type 1 skin have fewer nevi. ^[27] The argument is centered on the observations that flesh-colored nevi in such individuals are difficult to observe and that common acquired nevi are easily mistaken for freckles. ^[17]

In summary, epidemiologic data have shown that the largest numbers of common acquired nevi are found in males with type II skin, freckles, and high parental nevus counts. ^[4]

Common acquired melanocytic nevi are typically less than 1 cm (often < 6 mm) in diameter, with smooth and regular borders. Pigmented variants characteristically show evenly distributed pigmentation on physical and dermatoscopic examination. Depending on the size and elevation, common acquired nevi can present as macules, papules, or nodules.

Typically, junctional melanocytic nevi are pigmented and present as brown to brownish-black macules. In contrast, compound melanocytic nevi are elevated in relation to adjacent uninvolved skin and present as papules or nodules. Compared with junctional melanocytic nevi, compound melanocytic nevi are often lighter in color, ranging from tan to light brown. Intradermal melanocytic nevi often display no significant pigmentation, presenting as a flesh-colored papule or nodule.

Common acquired nevi obey the ABCDE rules of nevi (A symmetry, B order irregularity, C olor variation, size/D iameter, and E volutionary change). Deviation from these guidelines is cause for concern.

The following are considered in the differential diagnosis of benign melanocytic nevi:

• Atypical Mole (Dysplastic Nevus)

• Basal Cell Carcinoma

• Congenital Nevi

• Lentigo

• Malignant Melanoma

• Oral Neurofibroma

• Seborrheic Keratosis

Other conditions to consider include the following:

• Congenital melanocytic nevus

• Palisaded and encapsulated neuroma

Gross examination of common acquired nevi correlates with the clinical findings. Macules, papules or nodules should have smooth and regular borders. Pigmentation is typically darker for junctional melanocytic nevi and lighter for compound or intradermal melanocytic nevi.

The categorization of a common acquired nevus depends on the distribution and location of nevomelanocytic nests. In junctional nevi, the nests are situated at the tips and sides of the rete ridges closely opposed to the dermal-epidermal (DE) junction. In compound nevi, there is a combination of nests at the DE junction and within the dermis. Finally, in intradermal nevi, the nevomelanocytic nests are located solely within the dermis.

Nevus cytology is bland, and nuclear size is typically less than that of adjacent keratinocytes (see the image below). Also, nuclear membranes are regular in contour. Larger cells with small nucleoli are often seen from nevi of younger patients, but these are still within the realm of a benign melanocytic nevus.

Compound melanocytic nevi are simply a combination of junctional and dermal nevi. Nevomelanocytic nests are located at the DE junction in discrete nests, accompanied by an underlying collection of dermal nevomelanocytes (see the image below).

The junctional component of ordinary compound nevi should not extend beyond three rete ridges from the dermal component. The identification of lateral extension would define a “shoulder,” and an alternative diagnosis such as Clark ("dysplastic") nevus or melanoma should be considered.

The dermal component of compound nevi and intradermal nevi typically displays a characteristic finding known as histologic maturation. In this event, superficial type A nevus cells with voluminous cytoplasm and large nuclei “mature” to type B nevus cells with less cytoplasm and smaller nuclei as the lesion extends to deeper portions of the dermis (see the first image below). With further descent, type C nevus cells are encountered, which typically have scant cytoplasm and spindle-shaped nuclei (see the second image below).

Intradermal melanocytic nevi consist of nests of nevomelanocytes confined to the dermis (see the images below). Occasionally, intradermal nevi have focal junctional melanocytic hyperplasia, which may appear slightly atypical, with small nucleoli and nuclear enlargement. This finding is still within the realm of a benign melanocytic nevus.

Peculiar histologic findings are often seen in intradermal nevi or the dermal portion of compound nevi (see the images below). Such findings include neurotized nevus cell morphology, adipocyte “metaplasia,” metaplastic ossification, mucin or myxoid histology, amyloid deposition, multinucleation, and pseudovascular lacunae.

Epidermal hyperplasia overlying a melanocytic nevus is a phenomenon reported in up to one third of all melanocytic nevi (see the image below). ^[28] This finding can be seen in junctional, compound, or intradermal melanocytic nevi. Horn pseudocysts are often found within these lesions, simulating seborrheic keratosis, and hyperkeratotic infundibula often contain hair shaft fragments. ^[29]

Lack of maturation, lack of dispersion at the base of the lesion or finding dermal mitosis should alert the investigator to consider an alternative diagnosis, such as a malignant melanoma.

It is worth mentioning that certain nevi of special sites have unusual cytologic and architectural features, which could be wrongly interpreted as melanoma. These nevi are found in the genitals, the breast, the scalp, the ear, flexural regions, and conjunctival, umbilical, and acral locations. ^[30] Lesions submitted from these locations should be interpreted within this context.

The nevi of acral sites are often the most problematic because of inherent architectural disorder and the finding of central pagetoid spread in up to one third of cases (see the image below). ^[31] LeBoit coined the acronym MANIAC (Melanocytic Acral Nevus with Intraepidermal Ascent of Cells) for these lesions to emphasize the banality of pagetoid migration in these nevi. ^[32]

Immunohistochemical stains can be of great value in the assessment of a challenging melanocytic neoplasm. ^[33] S-100, MelanA/Mart-1(A103), tyrosinase(T311), and microphthalmia transcription factor (MITF) typically stain both the junctional and the dermal components of common acquired nevi, with sensitivities approaching 100%. ^{[34, 35, 36]}

The value of HMB-45, which targets the gp100 antigen within premelanosomes, lies in its characteristic staining pattern for common acquired nevi. HMB-45 primarily labels intraepidermal melanocytes, melanocytes located in the superficial papillary dermis, and melanocytes within the adventitial dermis surrounding adnexal structures. ^[37]

Common acquired nevi show a loss of HMB-45 expression with progressive descent into the dermis (see the image below), thus giving rise to the immunohistochemical maturation phenomenon. ^[37] Patchy or diffuse HMB-45 labeling of a melanocytic lesion should alert the investigator to an alternative diagnosis.

An additional immunohistochemical stain which may be useful in assessing common acquired nevi is the proliferation marker MIB1 (anti-Ki67). Labeling is generally limited to nevomelanocytes in the dermal-epidermal (DE) junction or the more superficial papillary dermis. ^[37] The dermal portion of common acquired nevi typically shows labeling in fewer than 5% of nevomelanocytes; values greater than 10% should clue the diagnostician to an alternative diagnosis.

Common acquired nevi are benign lesions; thus, little need be said about tumor staging and spread, except that benign nevus cells have been detected in lymph nodes taken out for staging of other malignant lesions. The bland-appearing nevomelanocytes are typically located within the capsule of the lymph node (see the image below). Any collection of atypical melanocytes within the lymphatic channels, sinuses or parenchyma of the lymph node should raise the diagnostic consideration of a metastatic malignant melanoma. ^[38]

The development of malignant melanoma from a preexisting melanocytic nevus is a well-described occurrence. A clinical history of a preexisting nevus at the site of a melanoma is reported in 19-85% of cases, and the contiguity of nevus cells with melanoma is observed in 4-72% of cases. ^[39]

The estimated likelihood that any given nevus will develop into a melanoma is roughly 1/100,000. ^[40] Nevertheless, increased numbers of common acquired nevi are associated with an increased risk of melanoma of the superficial spreading or nodular type. ^{[40, 41, 42]} Additionally, ultraviolet (UV) radiation is also attributed to development of de novo melanoma; thus, such individuals should be subjected to proper screening programs.

A cohort of 464 samples identified a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and has potential clinical applicability. ^[43]