Pathology and Molecular Features of Melanocytic Nevi and Melanoma
HISTOPATHOLOGY OF BENIGN MELANOCYTIC NEVI
Melanocytic nevi (MN) are benign neoplasms of melanocyte origin with a wide clinical and histopathologic heterogeneity (1,2). There are many subtypes of MN and discussion of all is beyond the scope of this chapter. We discuss a few of the most common subtypes of MN.
Common Melanocytic Nevus
Common MN are composed of nevomelanocytic nests and are classified as junctional, intradermal, and compound, according to the location of melanocytic nests. A junctional nevus consists of nests of melanocytes at the dermal–epidermal junction (Figure 2.1A). The architecture is regular with nests at the tips of rete ridges without bridging or fusion. The cytology of nevus cells is bland and uniform with nuclear size less than that of adjacent keratinocytes and regular nuclear membrane contours. Intradermal nevus contains nests of maturing melanocytes within the dermis (Figure 2.1B). Compound nevus shows histologic features of both junctional and intradermal nevus (Figure 2.1C).
Blue nevus (BN) is an intradermal nevus composed of spindle, dendritic, polygonal, or epithelioid pigmented melanocytes associated with abundant melanophages (Figure 2.2A). BN has a wide histologic spectrum and includes dermal melanocytosis, common, cellular, hypopigmented, and deep penetrating variants. The blue color clinically (Figure 2.2B) is due to the Tyndall phenomenon, attributable to the deep melanin in the dermis, and the preferential absorption of long light wavelengths by melanin and the scattering of shorter wavelengths, representing the blue end of the light spectrum. When BN arises in association with other types of nevi, it is designated as combined nevus. Metastatic melanoma may mimic BN.
Congenital nevi are divided into small (<1.5 cm), medium (1.5–20 cm), and large/giant (>20 cm) and can present at birth or soon thereafter. Histologically, they are composed of small monomorphous melanocytes splaying between collagen bundles and aggregating around blood vessels and adnexal structures (Figure 2.3). Larger congenital nevi may penetrate into deep dermis and underlying structures. There is a 4% to 10% increased lifetime risk of developing malignant melanoma (MM) in congenital nevi, especially in large types (3).
Halo nevus (HN) may be junctional, intradermal, or compound and is associated with a band-like papillary dermal infiltrate of inflammatory cells, predominantly lymphocytes, that infiltrates and obscures the melanocytes (Figure 2.4A). In later stages, the nevus cells involute and the papillary dermis displays fibrosis and pigment incontinence. Clinically, HN is surrounded by an area of depigmentation (Figure 2.4B).
Atypical (Dysplastic) Nevus
Atypical (dysplastic) nevi (AN) are a broad controversial category of nevi without a universal consensus regarding the criteria defining them. They are composed of melanocytes that are abnormal, but not malignant. AN may be junctional (Figure 2.5A) or compound (Figure 2.5B) and are characterized by varying degrees of cellular and architectural atypia; based on which they are designated as a mild, moderate, or severe degree of atypia.
Mild cytologic atypia is defined as melanocytes with hyperchromatic nuclei and inconspicuous nucleoli that are smaller than basal keratinocytes. Moderate cytologic atypia is defined as melanocytes with hyperchromatic nuclei with small nucleoli that are as large as basal keratinocytes (1–2 times the size of basal keratinocyte nuclei). Severe cytologic atypia is defined as enlarged melanocytes with hyperchromatic nuclei and prominent nucleoli that are larger than basal keratinocytes (>2 times than the nuclei of basal keratinocytes). The random nuclear atypia of melanocytes is characterized by pleomorphism (variability in size and shape) and anisochromatism (variability in color).
The architectural atypia in AN include asymmetry, papillary dermal fibroplasia, lentiginous pattern, irregular rete ridges, and bridging between them. Compound AN often show extension of their junctional component beyond the dermal component, referred to as shouldering. A variable lymphocytic infiltrate, referred to as host response, within the papillary dermis is a frequent component of AN. Atypical melanocytes are arranged as single cells and as variably sized nests along the dermal–epidermal junction at the sides and bases of the rete ridges. The papillary dermal fibroplasia may encircle rete ridges (concentric fibrosis) or be confined to the tips of the rete ridges as stacks of collagen fibers (lamellar fibrosis) (1,2,4–7).
There are no good criteria for clinical–pathologic correlation of AN, that is, nevi can look atypical clinically and appear banal histologically and vice versa.
Certain nevi of special sites have atypical cytologic and architectural features, which, if detected elsewhere, could be interpreted as AN or melanoma. These nevi are usually found in the genital area, breast, scalp, ear, flexural regions, conjunctiva, or umbilical and acral sites (8). Lesions from these locations should be interpreted within their context. Modification of the grading criteria is also necessary in kids, as there are age-related differences.
HISTOPATHOLOGY OF MALIGNANT MELANOMA
Microscopically, MM is asymmetrical, poorly circumscribed, and shows architectural and prominent cytological atypia. When MM is contained within the epidermis, it is defined as melanoma in situ (MIS; Figure 2.6A). Invasive MM is defined by involvement of the dermis in addition to the epidermis (Figure 2.6B). Characteristic features include pagetoid intraepidermal upward scatter of melanocytes, consumption of the epidermis, ulceration, variability of nests, shape and size, lack of maturation, lymphovascular invasion, and dermal mitoses, including deep and atypical mitoses. Cytologic features include atypia and pleomorphism, most commonly of epithelioid and spindle morphology (Figure 2.6C).
Pathology reports of melanoma should include several parameters important for MM staging. Histologic indicators of poor prognosis in melanoma are: increased Breslow thickness, ulceration, increased mitotic rate, regression, lymphovascular and perineural invasion, vertical phase growth, and microsatellitosis. The interpretation of tumor infiltrating lymphocytes is a debatable prognostic feature; however, its presence is thought to portray a better prognosis.
Tumor depth (Breslow thickness) is the most important prognostic feature that strongly correlates with survival, and is measured in millimeters (mm) from the top of the granular cell layer of the epidermis perpendicularly to the deepest part of the tumor invasion.
Tumor Clark level indicates the anatomical level of invasion. While assessment of Clark level has been removed from the latest edition of the American Joint Committee on Cancer (AJCC) cancer staging manual, many pathologists still list it in their report (Table 2.1).
The WHO Histologic Classification of Melanoma Includes (9):
• Superficial spreading melanoma (SSM): This is the most common subtype and accounts for two thirds of MM cases; it most often occurs in sun-exposed areas, most commonly on the back in males and on the legs in females. Histologically, they show atypical epithelioid melanocytes with abundant cytoplasm, nuclear pleomorphism, and prominent nucleoli, distributed as single cells or in clusters with prominent scatter (known as “buckshot or pagetoid scatter”) throughout all levels of the epidermis. Melanocyte proliferation can be seen extending over the tips of the papillae in continuity from one rete ridge to another. Adnexal involvement and consumption of the epidermis may be seen. Invasive component shows variable degrees of atypia and lack of maturation (Figure 2.7A).
• Nodular melanoma (NM): This accounts for 5% of MM and is often found on the trunk and limbs of patients in their 50s to 60s presenting as a rapidly enlarging nodule. Histologically, there is a proliferation with atypical pleomorphic round or epithelioid melanocytes with hyperchromatic nuclei forming a dermal nodule with upward epidermal involvement, but minimal adjacent epidermal spread or radial growth (Figure 2.7B).
• Clark level I—MM is in the epidermis only.
• Clark level II—MM invades into the papillary dermis.
• Clark level III—MM fills the papillary dermis.
• Clark level IV—MM invades into the reticular dermis.
• Clark level V—MM invades into the subcutaneous tissue.