Overview
Dysplastic (atypical, Clark) melanocytic nevi are acquired pigmented melanocytic proliferations of the skin with distinct clinical and histologic features. In the appropriate clinically setting dysplastic (atypical, Clark) melanocytic nevi are cutaneous markers for CDKN2A mutation and the development of familial and nonfamilial melanomas. [1, 2] Dysplastic melanocytic nevi, Clark nevi, and nevus with architectural disorder (NAD) are synonymous terms to describe this acquired melanocytic proliferation. The National Institutes of Health (NIH) consensus conference recommended these lesions be defined clinically as atypical nevi and histologically as NAD (see the following image), as well as assigned a grade of melanocyte atypia as mild, moderate, and severe, although some authorities prefer to divide as high or low grade, or do not grade at all. [1]

Dysplastic (atypical, Clark) melanocytic nevi appear most commonly on the trunk. Similar lesions on acral sites, breast, genitalia, and the scalp and forehead in children are not associated with the familial syndrome but share histological features with Clark nevi. [1, 3, 4, 5]
See Atypical Mole (Dysplastic Nevus) for more information.
Epidemiology
Dysplastic (atypical, Clark) melanocytic nevi are common, pigmented lesions in adults, most prevalent in patients younger than 30-40 years. [6, 7] The immense majority of dysplastic (atypical, Clark) melanocytic nevi appear after birth, although some lesions with these histologic features also display findings that are characteristic of congenital nevi (arrangement around skin adnexa and vessels, involvement of arrector pili muscle).
Dysplastic (atypical, Clark) melanocytic nevi are clinically dynamic lesions, with a decreased number of lesions associated with an increase in age. [6] Clinically recognizable dysplastic (atypical, Clark) melanocytic nevi range from 7% to 18%, whereas histologic features of nevus with architectural disorder (NAD) are present in approximately 10% to as high as 53% of the general population. [7, 8, 9, 10] In a cancer center patient population, dysplastic (atypical, Clark) melanocytic nevi may account up to 30% of pigmented lesions. [11]
Etiology
In general, the development of dysplastic (atypical, Clark) melanocytic nevi includes risk factors similar to those for melanoma. Genetic predisposition and mutations in the CDKN2A (p16INK4a) gene are important in the development of a subset of dysplastic (atypical, Clark) melanocytic nevi in patients with familial atypical multiple mole syndrome. [12] Genetic alterations in dysplastic (atypical, Clark) melanocytic nevi appear complex and include loss of tumor suppressor genes and altered function of oncogenes, housekeeping genes, growth factors, and extracellular matrix proteins.
The molecular events which direct melanocytic proliferation to the pathogenesis of dysplastic (atypical, Clark) melanocytic nevi formation from melanoma is unknown, but it appears to include a constellation of genetic, epigenetic, and environmental factors (eg, B-RAF mutation status, cell cycle protein expression, histone modifications, and ultraviolet radiation exposure), which may regulate cellular mechanisms that bypass cellular senescence. [13, 14] Molecular analyses have focused primarily on cutaneous melanomas; however, studies suggest that there may be alterations in the same set of susceptibility genes in dysplastic (atypical, Clark) melanocytic nevi and cutaneous melanoma. [15] A helpful review of the molecular aspects of dysplastic (atypical, Clark) melanocytic nevi is available by Hussein and Wood. [16]
In summary, dysplastic (atypical, Clark) melanocytic nevi may manifest from karyotypic alteration in chromosome 1p and 9p; allelic loss at chromosomes 1p, 9p, and 17p; loss of tumor suppressor genes p16/CDKN2A, TP53, and Melastatin; microsatellite instability; alterations in mismatch repair proteins expression; activation of B-raf, ras, and myc oncogenes; and alterations in extracellular matrix proteins (collagen type I, III, VI, tenascin, and fibronectin) and cytokines/growth factors. [16]
Clinical Features
Dysplastic (atypical, Clark) melanocytic nevi vary in size but are often larger than common nevi (on clinical inspection, usually >3.0 mm in diameter). [1] However, based on experience at large cancer centers such as the MD Anderson Cancer Center, dysplastic (atypical, Clark) melanocytic nevi < 3 mm in size may account for up to 30% of dysplastic nevi in a cancer center patient population. [11]
Dysplastic (atypical, Clark) melanocytic nevi demonstrate macular and/or papular components with irregular, ill-defined borders, variable tan to dark brown pigmentation with an erythematous base. [17] Examination of pigmented lesions with a Wood lamp or dermoscopy (epiluminescence microscopy) improves clinical detection and aids in the diagnosis of benign, suspicious, and malignant melanocytic lesions. Dermoscopic exam may demonstrate an abnormal, erratic pattern of pigment within dysplastic (atypical, Clark) melanocytic nevi lesions. [7]
Differential Diagnosis
The following are lesions are considered in the differential diagnosis of dysplastic (atypical, Clark) melanocytic nevi:
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Melanocytic Lesions With Severe Architectural Disorder
The clinical and histologic differential diagnosis of dysplastic (atypical, Clark) melanocytic nevi include common nevi, melanoma, Spitz nevi, nevi of special sites, and melanoma in association with a dysplastic nevus. Partial biopsies of melanoma may show dysplastic nevuslike features and caution is advised in the interpretation of any partial biopsy.
Evaluation of rete ridge pattern, epidermal thickness and distribution, and homogeneity of atypical melanocytes will aid in the diagnosis of lentigo maligna from dysplastic (atypical, Clark) melanocytic nevi, because lentigo maligna typically demonstrates attenuated rete ridges, whereas dysplastic nevi show elongated, distorted rete ridges with dermal fibrosis. [18] However, because some lentigo maligna lesions may have a focally preserved rete ridge pattern, we advise examination of the entire lesion in evaluating incomplete biopsies of large, pigmented, sun-exposed skin of older patients. [19]
Small lesions with severe architecture or a subgroup of lesions on the lower leg may share features of dysplastic (atypical, Clark) melanocytic nevi and melanoma in situ. [11, 20] The presence of dermal mitosis and upward migration of intraepidermal melanocytes are not prominent features in dysplastic (atypical, Clark) melanocytic nevi, and if encountered in a melanocytic lesion, a thorough examination and ancillary studies may become necessary for further classification and diagnosis.
Gross and Microscopic Findings
The gross appearance of dysplastic (atypical, Clark) melanocytic nevi is similar to the clinical findings of an irregular, macular or papular pigmented lesion with ill-defined borders. Lesions typically show 2 differently colored areas ("2-toned" nevi), a central, slightly elevated (papular) component surrounded by a flat (macular) region. The erythematous base is better visualized in vivo.
Nevi with architectural disorder (NAD) may be compound or junctional, and the histologic diagnosis requires a combination of architectural disorder and random cytologic atypia of melanocytes. The architectural disorder includes asymmetry, subepidermal fibroplasia, and a distorted rete ridge pattern with bridging between adjacent rete rides (see the image below). [21] Compound lesions have extension of the junctional component beyond the dermal nests of melanocytes, referred to as shouldering. A host response with variable dermal lymphocytic infiltrate is frequently a component of NAD.

Atypical melanocytes are disposed as nests along the dermal-epidermal junction and at the tips of the rete ridges. The subepidermal fibroplasia may encircle rete pegs (concentric eosinophilic fibrosis) or be confined to the tip of the rete pegs as stacks of collagen fibers (lamellar fibrosis) (see the following image). The random nuclear atypia of melanocytes is characterized by pleomorphism, anisochromatism, as well as variation in size, shape, and staining intensity. Grading of NAD as mild, moderate, and severe is based on the degree of cytologic atypia of the melanocytes and whether atypia is localized to the shoulder region or extends throughout the lesion. [9]

Mild cytologic atypia is defined as lesions with ovoid- to ellipsoid-shaped nuclei, that are smaller than basal keratinocytes, with hyperchromatic nuclei, and without a visible or small nucleoli, typically restricted to the shoulder region. [22]
Moderate cytologic atypia is defined as melanocyte nuclei as large as basal keratinocytes (1-2 times the size of basal keratinocyte nuclei), hyperchromatic, ellipsoid- or rhomboid-shaped, with a small nucleolus visible in the center of the nucleus, typically extending throughout the lesion..
Severe cytologic atypia is defined as enlarged, spindle- and epithelioid-shaped melanocytes with hyperchromatic nuclei of melanocytes that are typically larger than basal keratinocytes (2 times or greater than the nuclei of basal keratinocytes), with distinct nucleoli. [22, 23]
Nevi in small children tend to have large nests of nevus cells, large nuclear size, and a prominence of nucleoli. Modification of the grading criteria may become necessary, as age-related differences in nevus cells can be seen, especially in prepubertal children. [22] Furthermore, the degree of architectural disorder evaluated by circumscription, symmetry, cohesiveness of nests, suprabasal melanocytes, confluence, and single-cell proliferation positively correlates with cytologic atypia of melanocytes and provides additional information for clinical management. [24]
A study by Balu et al suggested the potential of multiphoton microscopy in distinguishing between benign and malignant melanocytic nevi. [25]
Immunohistochemistry
The use of immunohistochemistry when evaluating melanocytic lesions may become necessary when the distinction between nevi with architectural disorder (NAD) and melanoma is not readily apparent on hematoxylin and eosin (H&E) examination and the lesion demonstrates overlapping histologic features. The standard antibodies used in dermatopathology practice for these types of lesions include HMB-45 (anti-gp100), anti-MART1, and MIB1 (anti-Ki-67). The use of these antibodies allows further subjective evaluation of the melanocytic lesion, allows examination of the degree of pagetoid spread of cells in the epidermis, and evaluation of the dermal component for maturation sequence with respect to HMB-45 and the proliferative index as measured by MIB1. [26] These stains are not required in the majority of lesions.
Banal melanocytic lesions display loss of HMB-45 staining with descent into the dermis. In contrast, melanomas will demonstrate absence of maturation of the dermal component and a patchy pattern of labeling with HMB-45. NAD exhibit less than 1-5% labeling with MIB1 (anti-Ki-67), and reactive cells are generally located in the superficial dermis. Melanomas may demonstrate a proliferative rate up to 16.4% with MIB1 and absence of an orderly pattern of labeling in the dermis. [26, 27] Double-labeling with MART-1/Ki-67 enhances the evaluation of proliferative index in melanocytes, especially in lesions with a high number of background lymphocytes.
Prognosis
Dysplastic (atypical, Clark) melanocytic nevi occur in the setting of sporadic and familial melanomas, and a large number of nevi is a risk factor in development of cutaneous melanoma. [28, 29] Increased numbers of clinically dysplastic (atypical, Clark) melanocytic nevi have been associated with a greater risk for melanoma in some studies. [30] Some studies suggest that persons who develop high-grade nevi with architectural disorder (NAD) have a greater risk for melanoma. [22, 31] Some investigators regard dysplastic (atypical, Clark) melanocytic nevi as intermediate lesions of tumor progression. [32]
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Pathology of dysplastic (atypical, Clark) melanocytic nevi. Compound melanocytic nevus with architectural disorder and shouldering (S), or extension of the junctional component beyond the dermal nests of melanocytes (D). Rete ridges are irregular and distorted with bridging (B) and eosinophilic fibrosis (arrows). Scattered lymphocytic infiltrate is often present (*).
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Pathology of dysplastic (atypical, Clark) melanocytic nevi. Two histologic features of architectural disorder include: (A) concentric eosinophilic fibrosis (E), in which fibrosis encircles a rete peg; and (B) lamellar fibroplasia (L), in which the fibrosis is confined to the tip of the rete peg with stacks of collagen fibers. Nests of melanocytes in the dermal-epidermal junction demonstrate random cytologic atypia (arrows).