Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
KeywordsNevusMelanomaMelanocyticBasal cellSquamous cellMerkel cellLentigoActinic keratosisEpidermisDermisVerrucous
The discussion of the skin will be divided into three subsections: melanocytic tumors, nonmelanocytic tumors, and inflammatory disorders. Skin biopsies are usually performed because the clinician sees a lesion, such as a mass, a rash, or a macule. However, skin biopsies are also sometimes used to diagnose systemic conditions. Usually the history is enough to direct you to one of the major three categories. Inflammatory and systemic conditions are not usually diagnosed by the general surgical pathologist, but a working knowledge of their classification can be very helpful. Melanocytic lesions are also more and more the exclusive domain of dermatopathologists, but any surgical pathologist should at least be able to tackle the most benign and most malignant ends of the spectrum.
The grossing of skin biopsy specimens varies a bit by the shape, size, and purpose of the excision, but for diagnostic specimens of tumors, the margins must be entirely examined in perpendicular cuts. See your grossing manual, and consult with your attending, for the best way to cut in a specimen.
Melanocytes are specialized cells in the epidermis and elsewhere that are derived from neural crest cells. They have a neuralish, dendritic morphology and stain with S100 and Sox10, like peripheral nerve cells. They also produce melanin pigment, which is exported from the cell and taken up by surrounding epidermal cells. Normal melanocytes do not have much visible pigment; in fact, the cytoplasm is clear, as the pigment leaves the cell (Figure 28.1). Densely pigmented cells along the basal layer of the epidermis are usually basal keratinocytes, not melanocytes. It is this pigment distribution that creates shades of skin color.
Normal melanocyte and skin. A normal melanocyte (1) stands out within a clear halo of cytoplasm. The pigmented component of the skin is actually the basal keratinocytes (2), which absorb the melanin. Typical basket weave or orthokeratin is present (3).
Abnormal melanocytes can accumulate pigment, and this can be a useful clue in identifying dysplastic melanocytes (discussed below) or identifying an unknown metastasis as melanoma. However, there are plenty of melanomas with no melanin to be found, so do not rely on that. Also beware of the melanophage, spindly macrophages in the dermis full of chunky globs of melanin—they are eating it, not making it (Figure 28.2).
Melanophages in an intradermal nevus . The nevus cells (arrowhead) have focal small specks of pigment, but the macrophages digesting the excess melanin (arrow) stand out.
Become familiar with the melanocyte; spend a few seconds looking for them when you encounter normal skin. Melanoma is a treacherous area precisely because there are no strict diagnostic rules about when something is malignant and when it is not, and much of the diagnosis (in subtle cases) relies on recognizing atypical melanocytes that are up to no good. The only way to learn this skill is to see lots of normal melanocytes.
As a pathologist, you now know that a “mole” is a type of gestational trophoblastic disease, and you are sophisticated enough to refer to a bump on the skin as a nevus. However, the word nevus really does mean just a bump on the skin, and there are things called nevus that have nothing to do with melanocytes. In this chapter, we will just be discussing the melanocytic nevi.
A melanocytic nevus is a proliferation of benign melanocytes. It begins along the basal layer of the epidermis, where melanocytes live, and the very earliest manifestation of this is an increased number of melanocytes along the dermoepidermal junction (DEJ ) in a single layer. This produces a dark patch on the skin, and the lesion is called a lentigo simplex (Figure 28.3). The word lentigo or lentiginous refers to “along the DEJ ” and is used in several different contexts.
Lentigo simplex in acral skin. The dense thick keratin seen here is typical of acral skin (palms and soles). There is a linear proliferation of single benign melanocytes along the dermoepidermal junction (arrows).
The next step in the life cycle of a nevus is the proliferation of melanocytes into little nests, or theques, along the DEJ . These are technically intraepidermal, although it is sometimes hard to appreciate that. This lesion is called a junctional nevus , and it appears as little clusters of bland melanocytes hanging from the DEJ .
From there, the melanocytes may begin to proliferate down into the dermis. They do so as small nests, sheets, or single cells, and they grow in a lobular pattern. Cytologically they are bland, round, clear cells, and they tend to “mature” (become smaller and more bland) the deeper into the dermis they progress. They become so numerous that they make a little nodule in the skin, forming the classic “mole.” Most adults have 10–20 of them. A nevus with a dermal component plus a junctional component is called a compound nevus (Figure 28.4). Eventually, with age, the junctional component regresses, and you are left with just an intradermal nevus (Figure 28.5). These can be pedunculated, hyperkeratotic, or hair bearing. Fortunately, melanoma arising in a benign intradermal nevus is vanishingly rare.
Compound nevus. This nevus shows nests of nevocellular (melanocytic) cells attached to the dermoepidermal junction (DEJ) (arrow). A nevus with only DEJ nests would be a junctional nevus . In this example, as there are also nevus cells dropping down into the dermis (arrowhead), this is a compound nevus . In a compound nevus, the cells at the deepest point should appear slightly smaller and more bland than those at the DEJ (“maturation”).
Intradermal nevus. This exophytic nevus has only dermal nests of nevus cells (arrow). The lesion is roughly symmetric, and the cells are smaller and more mature at the base (arrowhead).
Histologic features that suggest a benign nevus:
Size <3 mm in diameter
Lateral borders defined by nests, not individual trailing melanocytes
Lack of atypia in the melanocytes (nuclei are no larger than a keratinocyte nucleus and have small dense nucleoli, if any; multiple nuclei are okay)
Maturation into the dermis
Chunky brown-black pigment
Other Benign Nevi
The common blue nevus consists of a diffuse scattering of pigmented, dendritic (stellate), single melanocytes in the dermis (Figure 28.6). They are mixed in with melanophages.
Blue nevus. Small, indistinct, pigmented cells are scattered throughout the dermal collagen (arrow). The cells are elongated and fusiform or stellate and do not make rounded nests like typical nevus cells. Some of the larger cells with chunky pigment are likely melanophages.
The Spitz nevus is usually found on the head and neck of children and adolescents. At low power, it is circumscribed and symmetric, and large nests of melanocytes are found between skinny elongated rete (Figure 28.7). Eosinophilic globules may be seen at the DEJ . The reason this lesion is so troublesome is that the melanocytes may be large, spindled, pleomorphic, or atypical and they may even show rare mitoses and pagetoid spread, all of which suggests melanoma. The distinction of Spitz nevus from rare pediatric melanoma, however, (or the variants of atypical Spitz nevus and spitzoid melanoma) is best left to the experts.
Spitz nevus . This nevus in a child shows nests of large, spindly melanocytes at the dermoepidermal junction (arrow) and rare melanocytes spreading up through the epidermis (arrowhead). In an adult, this pattern would be very worrisome.
Acral and genital nevi—nevi of the hands and feet, genital regions, and breasts—are allowed some atypical features. They may have more irregular placement of melanocytic cells and can even have occasional ascending cells mimicking pagetoid spread. However, they should not have cytologic atypia .
Most nevi are acquired during childhood to early adulthood, but some are congenital. To have congenital features means that the dermal melanocytes tend to track down the adnexal structures and along neurovascular bundles.
There are some nevi that begin to show some features more commonly associated with melanoma. These nevi are clinically distinct looking, and although they are not considered actual precursors to melanoma, patients with multiple dysplastic nevi are at significantly higher risk of developing melanoma. However, “dysplastic nevus” is a clinical diagnosis, and as pathologists, we merely describe the features we see. There are two components to dysplasia in this context: architectural disorder and atypia. These lesions are signed out as, for example, compound nevu s with architectural disorder and severe cytologic atypia . (However, in some texts, you will find this entity listed as lentiginous melanocytic nevus or Clark’s nevus.)
There are four features of architectural disorder: architectural disorder is not graded but is simply present or absent.
Lentiginous spread of atypical melanocytes (along the DEJ in a creeping line)
Shouldering (the lentiginous component is wider than the dermal component)
Bridging of rete (nests attached to adjacent rete ridges fuse; Figure 28.8)
Dysplastic nevus . At low power, elongated nests of spindly melanocytes are seen bridging across adjacent rete (arrow), and single melanocytes trail off to the lateral edge of the lesion (arrowhead). These are features of architectural disorder. Inset: atypical melanocytes with large nuclei and nucleoli are seen at the dermoepidermal junction.
Fibroplasia (a feathering of the dermal collagen that looks like pink cotton candy)
The features of cytologic atypia include the following:
Hyperchromatic nuclei, increased nuclear to cytoplasmic ratio
Large red nucleoli
Accumulation of dusty gray-brown melanin (see Figure 28.8)
Atypia is graded as mild, focally severe, or severe. In general, these nevi tend to be suspicious enough that you must take a few moments to prove to yourself that they are not melanoma.
The best way to think about melanoma is the presence of malignant melanocytes. Because melanocytes can proliferate in many ways and still be benign, it takes considerable experience to decide if a melanocyte is malignant or not. However, setting that aside for a moment, the types of melanoma include the following:
Melanoma in situ (MIS): malignant melanocytes along the DEJ and percolating up through the epidermis in a pagetoid fashion (something benign melanocytes do not do)
Lentigo maligna: a subtype of MIS in which malignant melanocytes proliferate only along the DEJ
Invasive melanoma: malignant melanocytes along the DEJ , pageting through the epidermis and invading the dermis
Superficial spreading melanoma : melanoma in a “horizontal growth phase,” meaning it is spreading laterally along the DEJ but also involves the dermis (clinically, this is a macular lesion [flat])
Nodular melanoma : melanoma with a “vertical growth phase,” meaning that it is primarily growing down into the dermis (almost like an intradermal nevus , but with malignant cells), producing a raised lesion
Lentigo maligna melanoma : invasive melanoma that has arisen in the setting of lentigo maligna
Most melanomas have both a horizontal and a vertical component, which is the classic irregularly shaped dark macule with a central raised or ulcerated papule.
Features of Malignancy
Unfortunately there is no single feature that can rule melanoma in or out. As with many types of neoplasia, there are certain features that suggest malignancy, and the presence of enough of them can convince you of the diagnosis. Many of these criteria are subjective and require experience, which is why dermatopathology is such a booming subspecialty these days.
On low power, look for the following:
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Poorly circumscribed, pleomorphic, discohesive nests of melanocytes
Shouldering (lateral spread) of atypical melanocytes
Pagetoid spread through the epidermis (Figure 28.9)
Melanoma . (a) Large, dark, irregular melanocytes can be seen infiltrating upward through the epidermis (arrowheads) in pagetoid fashion. If there were no dermal component, this would qualify as melanoma in situ. (b) Invasive melanocytes deep in the dermis. Large atypical nuclei with large nucleoli (arrowhead) plus the presence of mitoses (arrow) are diagnostic of invasive melanoma. Adjacent lymphocytes (asterisk left side of the field) are common.
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