I. BACKGROUND. Melanocytes are melanin-synthesizing cells derived from the neural crest. During the first 3 months of gestation, they migrate into the ectoderm where they normally occupy a space slightly beneath the basal keratinocytes. They can be differentiated from adjacent keratinocytes by their rounded and slightly hyperchromatic nucleus as compared with the more elongated or ovoid nucleus with evenly dispersed chromatin of the basal keratinocyte. In addition, melanocytes usually exhibit a pale often eccentric rim of eosinophilic cytoplasm and are separated from the neighboring basal keratinocytes and/or basement membrane by a clear space or halo (e-Fig. 40.1).* Occasionally, dendritic processes can be seen as they extend between the keratinocytes. The ratio of melanocytes to basal keratinocytes depends on the body site. On the trunk and extremities it is approximately 1:7 to 10, while the ratio on the face and external genitalia is about 1:3.
The main function of melanocytes is the production of melanin, a tyrosine-derived photoprotectant which converts UV radiation into heat, thus preventing UV-related DNA damage. Melanin is exported via melanosomes, which are membrane-bound and have an internal lattice-like structure. Melanin granules are deposited on the lattice, eventually obscuring this architectural feature. Melanin pigment found in the skin is classified as eumelanin (brown or black pigment) or pheomelanin (yellow-red pigment), the latter of which is rich in sulfur.
In addition to the general considerations for gross examination of skin specimens (Chap. 38), a complete description of the background skin color and the clinical “ABCDs” (see section on melanoma ) is required for biopsies or excisions of a pigmented lesion. Therefore, the size of the surface lesion, distance to or presence at the margin, color regularity or irregularity, and border, should all be included in the gross description.
Diagnosis of a melanocytic lesion is based on multiple architectural and cytologic criteria. In most cases, these microscopic features result in a specific diagnosis that reliably correlates with the anticipated biologic behavior of the melanocytic proliferation. Features associated with benignancy include symmetry, circumscription, maturation, predominance of nested melanocytes, cohesive nests of melanocytes, and melanocytes with regular nuclear borders and without nucleoli or atypical mitoses. A comparison of the histologic criteria for benign and malignant melanocytic proliferations can be found in Table 40.1. The status of the margins should be included routinely on all pathology reports of melanocytic proliferations, even in punch biopsy specimens. Although there admittedly is no consensus on this point, the margin status provides additional information that is often clinically useful.
Immunohistochemical stains can be helpful in distinguishing melanocytic from nonmelanocytic lesions, confirming nodal micrometastases, or demonstrating confluence or nonconfluence of melanocytes. Although several stains are available, including S100, Melan-A (MART-1), HMB-45, MITF, and NKI-C3, no immunostain is capable of reliably differentiating malignant from benign melanocytic lesions.
TABLE 40.1 Histopathologic Features in the Differential Diagnosis of Benign and Malignant Melanocytic Proliferations
– or ±
– or ±
Regular nuclear border
Absence of nucleoli
Because of the histologic diversity of melanocytic lesions, there are instances in which the morphologic features that support a benign diagnosis (nevus) and those that support a malignant diagnosis (melanoma) seem to be equally represented. Occasionally, even among experts, there is no consensus regarding the benign or malignant nature of a melanocytic lesion based on the histomorphology. In these cases, as in definitive melanomas, a complete excision is necessary, and consultation with a pathologist or dermatopathologist either within the department or from an outside institution should be sought.
When a melanocytic lesion exhibits borderline features, chromosomal studies are sometimes helpful to determine a definitive diagnosis. Two main methods are utilized for this purpose: comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). It has been shown that most nevi maintain chromosomal stability and therefore do not exhibit DNA gains and/or losses. Melanomas, by comparison, have variable gains and losses across multiple genes, while Spitz nevi have either a normal genotype or an isolated amplification of chromosome 11p.
II. BENIGN MELANOCYTIC PROLIFERATIONS. Any nevus, by definition, is benign. A melanocytic nevus, when the histologic diagnosis is given without modifiers such as “with severe atypia,” is a benign proliferation/hamartoma of melanocytes in the epidermis, epidermis and dermis, or dermis alone. In general, a melanocytic nevus is a small (<6 mm), symmetric, well-circumscribed proliferation of nested melanocytes, and the melanocytes that are deepest in the dermis are smaller than superficial melanocytes, a process known as maturation. The basic histologic criteria, as shown in Table 40.1, apply to most nevi. However, there are multiple histologic subtypes of nevi, some with exceptions to these criteria. Therefore, knowledge of the histologic subtypes, and the exceptions they present, is helpful. A summary of these variants and their malignant counterparts is provided in Table 40.2 and The World Health Organization (WHO) classification of melanocytic tumors is given in Table 40.3.
A. Lentigo simplex
1. Clinical: It is an acquired pigmented lesion that is small in size and has a flat appearance. It is evenly colored and can usually be found on sun-exposed skin in persons <40 years of age.
2. Microscopic: Rete are long and slender and have increased numbers of cytologically unremarkable melanocytes, without aggregates (nests) of melanocytes. Melanin pigment is increased in the basal keratinocytes (e-Fig. 40.2).
B. Junctional melanocytic nevus
1. Clinical: It is an acquired pigmented lesion that is small in size and has a flat appearance. Like lentigo simplex, it is evenly colored and can usually be found on sun-exposed sites.
TABLE 40.2 Histologic Types of Melanocytic Nevus and Their Borderline or Malignant Counterpart
Borderline or malignant
Junctional melanocytic nevus with or without AD
Melanoma in situ, lentiginous or superficial spreading type
Compound melanocytic nevus with or without AD
Melanoma of nevoid type, melanoma arising in nevus or malignant melanoma
Dermal melanocytic nevus
Metastatic or recurrent melanoma
“Spitzoid” melanoma or “borderline” atypical Spitz tumor
Pigmented spindle cell nevus of Reed
Spindle cell melanoma
Deep penetrating nevus
Spindle cell melanoma
Melanoma with intense host reaction
Balloon cell nevus
Melanoma with balloon cell features
Congenital nevus with proliferative nodule(s)
Melanoma arising in congenital nevus
Melanoma with regression
Cellular blue nevus
Spindle cell melanoma or malignant cellular blue nevus
AD, architectural disorder.
2. Microscopic: Nests/aggregates of melanocytes are present at the tips of the rete. There may be increased numbers of cytologically unremarkable melanocytes along the sides of the rete, but there is no confluent growth of melanocytes (e-Fig. 40.3).
3. Note: The presence of a purely junctional nevus should be viewed with some concern in an individual >50 years. In these cases, it is helpful to take into consideration the size of the lesion and also to determine whether the junctional population of melanocytes has a confluent or nonconfluent pattern of proliferation. The diagnosis of junctional nevus should be made hesitantly on skin with significant solar elastosis.
C. Compound melanocytic nevus
1. Clinical: It is an acquired pigmented lesion that is small in size. It is usually slightly raised, evenly colored, and is normally found on sun-exposed skin. However, like intradermal nevi, it may have a variety of configurations from polypoid to papillomatous.
2. Microscopic: This nevus has features of both a junctional and an intradermal nevus. There are nests/aggregates of melanocytes at the tips of the rete and nests/aggregates of melanocytes in the dermis. The proportion of epidermal melanocytes to dermal melanocytes is variable (e-Fig. 40.4).
3. Note: Care should always be taken to make certain that the deep dermal melanocytes are smaller, do not have nucleoli, and lack mitotic figures. A second population or clone of nevoid cells should be viewed with concern. There is no more diagnostically treacherous lesion than the nevoid or nevus-like melanoma.
D. Intradermal melanocytic nevus
1. Clinical: An intradermal melanocytic nevus is a raised (papular), nonpigmented lesion that may have a variety of configurations from polypoid to papillomatous, reflecting in part the appearance of the epidermis. It can be mistaken clinically for a skin tag (fibroepithelial polyp) or a basal cell carcinoma.
2. Microscopic: Nested and individual melanocytes are found only in the dermis (e-Fig. 40.5). The dermal component of compound or intradermal nevi can show so-called neurotization with a resemblance to a neurofibroma, contain
spaces with a pseudovascular appearance, and have scattered multinucleated cells as a feature of presumed senescence.
TABLE 40.3 WHO Histologic Classification of Melanocytic Tumors
Superficial spreading melanoma
Melanoma arising from blue nevus
Melanoma arising in a giant congenital nevus
Melanoma of childhood
Benign melanocytic tumors
Congenital melanocytic nevi
Proliferative nodules in congenital melanocytic nevi
Dermal melanocytic lesions
Nevus of Ito and Ota
Cellular blue nevus
Melanotic macules, simple lentigo, and lentiginous nevus
Persistent (recurrent) melanocytic nevus
Pigmented spindle cell nevus (Reed)
From: Weedon D, LeBoit P, Burg G, et al., eds. World Health Organization Classification of Tumours. Pathology and Genetics. Skin Tumours. Lyon, France: IARC Press; 2005. Used with permission.
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