Acquired Melanocytic Nevi

2  Acquired Melanocytic Nevi Pedram Gerami and Klaus J. Busam

OUTLINE Origin of Melanocytes, 8 Ultraviolet (UV) Radiation and Nevi, 8 Clinical Findings, 8 Common Acquired Junctional Melanocytic Nevi, 8 Common Acquired Compound Melanocytic Nevi, 9 Common Acquired Intradermal Melanocytic Nevi, 9 Histopathologic Findings, 9 Common Acquired Junctional Melanocytic Nevi, 9

Acquired Compound and Intradermal Melanocytic Nevi, 10 Halo and Eczematous Nevi, 14 Dysplastic Nevi, 14 Differential Diagnosis, 22 Melanocytic Nevus With Atypical Features Versus Melanoma In Situ Associated With a Nevus, 22 Dysplastic Nevus Versus Melanoma, 22

Acquired melanocytic nevi are thought to result from activation of oncogenes either through an activating mutation or translocation, allowing for clonal proliferation of the affected melanocytes. In the majority of common acquired, including the so-called dysplastic, nevi, the initiating oncogenic event is either an activating mutation in BRAF (80%) or NRAS (5%). Mutations in GNAQ or GNA11 are associated with blue nevi, whereas most Spitz nevi harbor translocations. Melanocytic nevi, including acquired nevi, typically contain nests of melanocytes, which are defined as aggregates of at least three melanocytes. They can populate different compartments of the skin. When a benign melanocytic proliferation with nests is confined to the epidermis, it is referred to as a junctional melanocytic nevus. When in addition to junctional nests melanocytes are also present in the dermis, a benign lesion is referred to as a compound nevus. Exclusive intradermal growth of benign melanocytes represents an intradermal nevus.

melanocyte rather than epidermal melanocyte. It seems less likely that these nevi would have progressed through a junctional phase. The so-called congenital pattern of compound melanocytic nevi is more plausibly explained by a dermal origin of lesional melanocytes. On the other hand, those nevi developing later in life that begin as macular lesions in a sunexposed distribution are probably derived from a junctional melanocyte and may follow the pattern of “Abtropfung” as proposed by Unna.

ORIGIN OF MELANOCYTES The origin of melanocytic nevi has been debated for a long time.1-6 In 1893 Unna suggested that epidermal melanocytes were the source of common acquired nevi and that most nevi started as junctional nevi from which some melanocytes would migrate to the superficial dermis to form compound nevi. He named this process “Abtropfung” (dropping off). Accordingly, it was assumed that purely intradermal nevi result after involution of the junctional component. An alternate theory proposes that dermal melanocytic precursor cells may be the source of many melanocytic nevi and that in compound melanocytic nevi the dermoepidermal junction is populated from below (so-called Hochsteigerung, or climbing up). Studies on nevi at various ages have shown that compound and intradermal melanocytic nevi outnumber junctional nevi in children.7 Furthermore, junctional melanocytic nevi occur more frequently in older individuals. It is therefore likely that acquired nevi displaying a predominantly intradermal growth in a pattern that has historically been associated with congenital nevi result from an initiating oncogenic mutation in a dermal

8

ULTRAVIOLET (UV) RADIATION AND NEVI Many studies have documented a relationship between exposure to ultraviolet radiation and the development of melanocytic nevi. This includes an association between total nevus counts and/or distribution of nevi with a history of sun exposure.7,8 The most common driver mutation in common acquired nevi involves BRAF, which is found in approximately 80% of these nevi.9 Interestingly, mutations in BRAF are not Ultraviolet B (UVB)-induced DNA photoproducts. Among melanomas, there is a link of UV-related melanomas with particularly intense intermittent bouts of UV and BRAF mutation. However, among nevi, BRAF mutation may be seen in both UV-related and non–UV-related nevi.10,11 They are more frequent in compound than junctional nevi.9,12,13 Although ultraviolet light plays a role in the development of nevi, twin studies have demonstrated a significant heritability component to total nevus counts.14,15 Monozygotic twins had significantly greater similarity in total nevus counts compared with dizygotic twins.

CLINICAL FINDINGS Common Acquired Junctional Melanocytic Nevi Common acquired junctional melanocytic nevi are uncommon in childhood and are typically seen in adults.16 Clinically these are typically flat, circumscribed, small macular lesions with variable pigmentation. By dermoscopy they usually have a reticulated pattern (Fig. 2.1). The reticulation is a result of the accumulation of the pigment along the

CHAPTER 2  Acquired Melanocytic Nevi

Keywords acquired melanocytic nevi dysplastic nevi junctional nevi compound nevi melanoma in situ associated with a nevus melanoma halo nevi eczematous nevi intradermal nevi ordinary nevus common nevus

8.e1

CHAPTER 2  Acquired Melanocytic Nevi

Fig. 2.1  Junctional melanocytic nevus—dermoscopy: fairly symmetric and orderly reticulated pattern.

9

Fig. 2.3  Clinical appearance of a predominantly intradermal melanocytic nevus, presenting as a predominantly amelanotic nodule.

A

Fig. 2.2  Melanocytic Nevus With Globular Pattern on Dermoscopy. This pattern often correlates to a banal compound or intradermal nevus.

rete ridges, and the clear spaces between the network correspond to dermal papillae where there is usually less pigment in these lesions.

Common Acquired Compound Melanocytic Nevi The growth of melanocytes in the dermis typically elevates the overlying epidermis and leads to the formation of papules. The lesions may be pigmented, display the same color as the adjacent skin, or be reddish. They are usually small and circumscribed. Some lesions may be polypoid or pedunculated. The epidermal surface may be smooth or verrucous/ papillomatous. Dermal nevi, if pigmented, may have a granular or globular dermoscopic appearance or the appearance of granules on the background of a reticulated network (Fig. 2.2).

Common Acquired Intradermal Melanocytic Nevi Like compound nevi, the presence of intradermal growth is often associated with a raised papule with a range of colors from pink to

B Fig. 2.4  Pigmented Junctional Melanocytic Nevus. (A) Silhouette of a small circumscribed macule. (B) Within the lesion there is basal layer hyperpigmentation. There is a proliferation of melanocytes as solitary units and small nests, preferentially displayed at the tips of rete ridges. The lesion is mildly inflamed and associated with melanophages in the superficial dermis.

brown. Some lesions are plaquelike. Others are nodular (Fig. 2.3). Some may simulate a skin tag. On dermoscopy the intradermal nests give the lesion a granular or globular appearance.

HISTOPATHOLOGIC FINDINGS Common Acquired Junctional Melanocytic Nevi Junctional nevi are benign melanocytic neoplasms in which nests are seen exclusively in the epidermis, predominantly at the dermoepidermal junction (Figs. 2.4 to 2.6). Features of a benign junctional melanocytic proliferation include relatively small size, symmetry, ordered growth with relatively even placement of nests, sharp lateral

10

SECTION I  Benign Cutaneous Melanocytic Proliferations

Fig. 2.5  Lentiginous Junctional Melanocytic Nevus. Melanocytes are present at the dermoepidermal junction associated with basal layer hyperpigmentation. Melanocytes are predominantly clustered around the rete ridges, forming small nests.

Fig. 2.7  Compound Melanocytic Nevus. Well-formed junctional nests are present at the tips of epidermal rete ridges. Cytologically bland melanocytes are present as small clusters and solitary units in the superficial dermis.

TABLE 2.1  Melanocyte Pagetosis in

Common Acquired Nevi Scenario Trauma

Sunburn Nevi of special site Fig. 2.6  Junctional Melanocytic Nevus. Melanocytes are predominantly displayed as well-formed nests at the dermoepidermal junction.

demarcation, and bland cytology. The term lentiginous junctional nevus is used for junctional nevi in which the epidermis has lentigo-like features with elongated and pigmented epidermal rete ridges. In lentiginous nevi, there is typically a proliferation of solitary units and nests. The melanocyte nests are mainly aggregated to the tips of the rete ridges (Fig. 2.5). Other junctional nevi may display a predominance of well-formed nests (Fig. 2.6). In most lesions, there is a mix of solitary units and nests of melanocytes at the dermoepidermal junction. On occasion (e.g., with trauma, acral, or congenital nevi) melanocytes of junctional nevi may also be present in the spinous cell layer (Table 2.1).

Acquired Compound and Intradermal Melanocytic Nevi Compound nevi are benign melanocytic proliferations that, in addition to junctional melanocyte nests, have melanocytes also in the dermis (Fig. 2.7). In intradermal nevi the melanocytes reside only in the dermis. Junctional nests are absent, but on occasion the epidermis overlying the dermal nevus may show hyperpigmentation and/or slight hyperplasia

Recurrent nevi

Clinical Diagnostic Histologic Clues Diagnostic Clues History of trauma/surgery Parakeratosis, hemorrhagic crust, subepidermal hemorrhage, fibrosis History of sunburn Apoptotic keratinocytes Nevi on the ear, acral Often have large nests sites, breast, genitalia, closely opposed to one other. another, oftentimes on the sides of or inbetween rete ridges; pagetosis is mild and mostly central or above nests. History of a previously Confluent lentiginous excised nevus, nevus growth and mild occuring within a scar pagetosis confined to the epidermis above the scar

of solitary units of melanocytes. Two common patterns of acquired nevi are referred to as Miescher and Unna nevus. Unna nevi are exophytic with a mamillated surface with nests of melanocytes in the papillary dermis (Fig. 2.8). Junctional nests may also be seen. Miescher nevi are smooth, dome-shaped papules that are typically entirely intradermal (Fig. 2.9). Common acquired compound and intradermal melanocytic nevi tend to be relatively small (<4 mm) and circumscribed (see Figs. 2.8

CHAPTER 2  Acquired Melanocytic Nevi

11

A

A

B Fig. 2.9  Miescher Nevus. (A) Papule with smooth surface. (B) Intradermal melanocytic nevus.

B Fig. 2.8  Predominantly Intradermal Melanocytic Nevus (Unna Nevus). (A) Exophytic growth with slightly papillomatous surface. The silhouette of the lesion is fairly symmetric. (B) Evidence of maturation: There is a change in the cytologic appearance of the melanocytes from the superficial to deep part of the lesion. There is a transition from superficial large epithelioid cells to smaller epithelioid cells and then fusiform cells at the base. The melanocytes are uniformly bland.

Fig. 2.10  Compound Melanocytic Nevus. The lesion displays the silhouette of a small superficial plaque. There is slight asymmetry, but the lesion is well circumscribed and predominantly composed of wellformed nests of cytologically bland melanocytes.

and 2.9). Most lesions display a fairly symmetric silhouette, but some minor asymmetry and irregularity in growth pattern is not uncommon among lesions selected for biopsy and microscopic review (Figs. 2.10). Intradermal melanocytes (of compound or entirely intradermal nevi) typically show features of zonation, which is often referred to as “maturation” (Figs. 2.11 and 2.12). This involves a decrease in size of nests and individual melanocytes from the superficial to the deep part of the lesion. Often this is accompanied by a morphologic change from large epithelioid appearance superficially to small epithelioid lymphocyte-like and fusiform schwannian (neural) at the base. These various cytomorphologies have been designated as type A melanocytes (epithelioid), type B (lymphocyte like), and type C (neural). A similar

change (“biochemical maturation”) can be seen for melanin pigment: if present, it tends to be most prominent in epidermal and superficial dermal melanocytes with loss of visible pigmentation with descent to the base of the lesion. Other findings commonly seen in acquired nevi include neurotization (Fig. 2.13), fatty metaplasia (Fig. 2.14), stromal edema (Fig. 2.15), and pseudovascular changes (Fig. 2.16). Additional features that may be seen include variable degrees of stromal fibrosis and/or inflammation. In some lesions there may be peculiar cytologic alterations: some or many melanocytes may display a pale, clear, or foamy cytoplasm or oncocytic changes. When melanocytes have abundant clear cytoplasm, this phenotype is referred to as balloon cell change.

12

SECTION I  Benign Cutaneous Melanocytic Proliferations

A B Fig. 2.11  Biochemical Maturation. (A) Intradermal melanocytic nevus. (B) Melanocytes in the superficial dermis and pigmented. The pigment is lost with descent into the mid and deeper dermis.

A

B

C

Fig. 2.12  Zonation (Maturation). (A) Type A melanocytes typically located in the superficial portion of a nevus. (B) Type B (lymphocyte-like) melanocytes typically located in the mid dermis underneath type A cells. (C) Neurotized type C spindle cell melanocytes.

CHAPTER 2  Acquired Melanocytic Nevi

A

B Fig. 2.13  Neurotized Miescher Nevus. An intradermal nevus involves the stroma surrounding a folliculosebaceous unit. (A) Juxtaposition of melanocytes with neural features and a few conventional type B melanocytes. (B) Higher magnification highlights the neural differentiation of the deeper melanocytes with nests simulating a nerve fascicle.

A

B Fig. 2.14  Melanocytic Nevus With Fatty Metaplasia. (A) Silhouette of the lesion highlighting extensive fatty changes throughout the lesion. (B) Cytologically bland small epithelioid melanocytes in collagenous and fatty stroma.

13

14

SECTION I  Benign Cutaneous Melanocytic Proliferations

A B Fig. 2.15  (A) Melanocytic nevus with edema and vascular ectasia. (B) Ectatic vessels with adjacent cytologically bland small epithelioid melanocytes in edematous stroma.

The clinical appearance and histologic picture of melanocytic nevi may also be altered because of a collision with another lesion or inflammatory process, such as seborrheic keratosis, basal cell carcinoma, or a folliculitis (Fig. 2.18).

Halo and Eczematous Nevi

Fig. 2.16  Melanocytic nevus with discohesion between intradermal melanocytes leading to the formation of pseudovascular changes.

Most common acquired or intradermal melanocytic nevi lack mitotic figures. However, some can be seen during an active growth phase, in particular during childhood or pregnancy. When mitoses are present in a nevus, they are typically located in the superficial dermis (Fig. 2.17; Table 2.2). Nuclear atypia in dermal melanocytes of compound or intradermal nevi is generally low grade in appearance. In some cases the more superficial nests may have slightly enlarged nuclei approximately the size of keratinocyte nuclei or even larger with prominent nucleoli, but with descent these cells become smaller and nucleoli become less apparent. Some cells may show senescent atypia in which single or small aggregates of cells have enlarged hyperchromatic, smudgedappearing nuclei, and/or nuclear pseudoinclusions. Enlarged hyperchromatic nuclei of nevi not infrequently have a tetraploid or near tetraploid karyotype.17 Occasionally in common acquired nevi there is a small subpopulation of melanocytes with different cytologic features, a phenomenon referred to as a combined nevus. These lesions are discussed in more detail in Chapter 9.

Some nevi invoke a host response with a brisk infiltrate of lymphocytes and histiocytes extending into the melanocytic nests. Morphologically this may or may not correlate with a so-called halo phenomenon or halo nevus, which refers to the clinical finding of circumferential depigmentation or hypopigmentation around a pigmented nevus (Fig. 2.19). The histopathologic correlate of hypopigmentation may be a bandlike lymphocytic infiltrate or features of regression (stromal edema, fibrosis, hypervascularity) (Fig. 2.20). The inflammation can sometimes be so dense that an immunostain is needed to assess the growth pattern of the lesional melanocytes. At a later stage, inflammation and some lesional melanocytes may be replaced by fibrosis, which is typical for a partly regressed melanocytic nevus (Fig. 2.21). Such lesions may display architectural disorder and atypia of melanocytes at the dermoepidermal junction. The intradermal melanocytes tend to be bland and show features of maturation. If a melanocytic nevus is associated with features of eczema (spongiotic or psoriasiform and spongiotic dermatitis), it may be referred to as Meyerson or eczematous nevus. Various types of acquired banal melanocytic nevi are listed in Table 2.3.

Dysplastic Nevi The so-called dysplastic nevus is a variant of an acquired melanocytic nevus. Other terms include Clark nevus or melanocytic nevus with architectural disorder and atypia. Given the controversy surrounding the term and the significance of this nevus type, two issues need to be discussed: the risk of transformation to melanoma and the level of risk conferred for melanoma in a separate site for patients with nevi classified as dysplastic. The term dysplastic nevus was originally used to describe large irregular nevi in patients with familial melanoma, with the assumption that these lesions had considerable risk for transformation to melanoma.18 Following the paradigm of a stepwise model of tumor progression of some epithelial neoplasms, with an evolution described as mild, moderate, severe dysplasia, then carcinoma, the dysplastic nevus

CHAPTER 2  Acquired Melanocytic Nevi

15

B

A Fig. 2.17  Mitotically Active Melanocytic Nevus. (A) Silhouette of a banal intradermal melanocytic nevus. (B) Cytologically bland melanocytes. A rare mitotic figure is seen in this field. Ten mitotic figures were found in this nevus.

TABLE 2.2  Clinical and Pathologic Features of Acquired Nevi Versus Melanoma Common Acquired Nevi

Dysplastic Nevi

Melanoma

Clinical findings

• Diameter usually ≤ 6 mm • Usually only 1 or 2 colors • Symmetry, particularly at dermoscopic level • Round or oval shaped • Well-demarcated border

• Asymmetry • Irregular borders • Asymmetry • Variable color • Diameter often >6 mm Note: These features overlap with melanoma, but the extent of irregularity is less than in melanoma

• Asymmetry • Irregular borders • Heterogeneity in color • Diameter often >6 mm • Recent change

Dermoscopic findings

Uniform • Reticular • Granular Globular patterns

Often has reticulated network with some atypical features such as • Branched streaks • Areas of widened network • Thick or thin lines within the network Overlying granules or globules may be seen, which are typically relatively uniform in color and relatively evenly distributed.

• Asymmetric and irregular network • Eccentrically placed pigment blotch • Presence of streaks • Irregular pigment granules or globules with variable size and color • Blue-gray veil Asymmetrically placed chrysalis, inverse pigment pattern, regression structures or vascular hue

Histologic findings

Common Findings Unna nevus • Typically exophytic with a mammillated surface • Compound nests of nevomelanocytes with maturation Miescher nevus • Smooth dome-shaped papules • Mostly intradermal with maturation

Major criteria include • Shouldering • Lentiginous growth or epithelioid cell pattern Minor criteria include • Lamellar fibroplasia • Neovascularization • host response • Bridging of nests Key features different from melanoma include: • Nests predominate • Circumscription • Areas of epidermal effacement are small • Pagetosis absent or only focal • Nuclear atypia focal and random

Typical findings • Marked asymmetry in silhouette, growth patterns, cytology, or pigment distribution • Predominance of single cells over nests • Ill-defined periphery • Broad zone of effacement of epidermal rete ridges (“consumption of the epidermis”) • Prominent pagetosis • Expansile and irregular nests • Uniform high-grade nuclear atypia

16

SECTION I  Benign Cutaneous Melanocytic Proliferations

B

A Fig. 2.18  (A) Melanocytic nevus associated with folliculitis. (B) Aggregates of bland melanocytes are located adjacent to suppurative inflammation.

TABLE 2.3  Morphologic Variations of

Common Acquired Melanocytic Nevia Morphologic Variant Mitotically active nevus

Neurotized nevus

Balloon cell nevus Fig. 2.19  Halo Nevus. Pigmented macule surrounded by a hypopigmented rim leading to a so-called fried egg appearance.

was proposed as an intermediate step lesion between ordinary nevus and melanoma. However, there are no compelling data that suggest that dysplastic nevi are eminent precursors of melanoma or have a much higher risk for transformation to melanoma than do common acquired or congenital nevi. In fact, the most common nevus remnant seen in association with melanoma is the common acquired nevus.19 Considering the large number of dysplastic nevi and the relatively small number of melanomas arising in association with dysplastic nevi, it can be concluded that the rate of progression from dysplastic nevus to melanoma is very low.20,21 Although the most common initiating driver mutations in dysplastic nevi are BRAF and NRAS mutations, as in other common acquired nevi, there is evidence that dysplastic nevi may also have loss of heterozygosity and P53 or CDKN2A.22

Sunburn nevus

Ancient/senescent nevus

Halo nevus

Meyerson/eczematous nevus a

Histologic Features • Common during pregnancy • Typically 1–2 mitoses/mm2; sometimes more. Mitoses tend be located superficial portion of the lesion • Schwannian cytology • Wagner-Meissner corpuscles may be present • Spindle cells usually lack expression of Melan-A/MART1 • Lesional melanocytes with pale or clear cytoplasm • Nuclear atypia may be present • Suprabasilar melanocytes and apoptotic epithelial cells • Clinical history of recent sun exposure or sunburn • Enlarged hyperchromatic basophilic nuclei • Absence of mitotic activity • FISH studies of melanocytes with enlarged nuclei often reveal tetraploidy • Dense lymphocytic infiltrate • Variable fibrosis • Variable edema and dermal hypervascularity • Melanocytic nevus associated with features of eczema

Traumatized, recurrent, and combined nevi are described elsewhere.

CHAPTER 2  Acquired Melanocytic Nevi

17

A

C

B

Fig. 2.20  Histopathology of a Halo Nevus. (A) The lesion displays a circumscribed symmetric silhouette. There is a central densely inflamed compound melanocytic nevus. It is flanked on both sides by features of regression (edema, hypervascularity, lack of melanocytes). (B) The dense inflammation makes it difficult to assess the cytology of the lesional melanocytes. (C) Areas within the lesion with less inflammation reveal cytologically bland melanocytes with evidence of maturation.

Fig. 2.21  Partly Regressed Melanocytic Nevus. There is intralesional fibrosis and partial loss of melanocytes.

“dysplastic” nevus should be viewed as a variant of a benign melanocytic nevus. The main challenge is its diagnostic distinction from melanoma (more difficult than the distinction of melanoma from banal nevus). In 1991 the World Health Organization (WHO) created a definition for dysplastic nevi based solely on histologic features that included major and minor criteria.24 The definition was based only on histologic features, because several studies have shown that nevi which clinically appear to be common acquired nevi often have features originally considered to be unique to dysplastic nevi by microscopy. To meet criteria for dysplastic nevus, the lesion had to satisfy both of the two major criteria and at least two of the four minor criteria:

Major Criteria In a study of melanomas associated with nevi, it was shown that lesional melanocyte populations with clearly benign features typically showed mutations only in BRAF, whereas in transition areas with more intermediate histologic features, in addition to either BRAF or NRAS mutations, several other mutations were found and that the mutational burden increased as the morphologic changes approached melanoma.23 These findings suggest that in those nevi transforming to melanoma there are often morphologic intermediaries with intermediate levels of mutational burden. However, it would be premature to extrapolate this observation to dysplastic nevi unassociated with melanoma. It does not imply that a clinically stable dysplastic nevus has a significantly greater risk of transformation to melanoma than does a stable common acquired nevus. Although it is possible that future studies may be able to assign different risks for progression to different types of nevi, at the current time risk stratification of nevi is largely speculative. In our view, the

1. Basilar proliferation of atypical melanocytes that must extend at least three rete ridges beyond the dermal component 2. Organization of this proliferation in a lentiginous or epithelioid cell pattern

Minor Criteria 1. Lamellar fibrosis or concentric eosinophilic fibrosis 2. Neovascularization 3. Host response 4. Fusion of rete ridges As is evident from the previous criteria, most of the histomorphologic features used to define lesions as “dysplastic” are related to the junctional growth of the neoplasm. This includes shouldering, which is the extension of the junctional component at least three rete ridges beyond the dermal component (Fig. 2.22). The junctional nests are also often encompassed

18

SECTION I  Benign Cutaneous Melanocytic Proliferations

by fibroplasia that can be either eosinophilic fibroplasia or lamellar fibroplasia, which has a more onion skin appearance of fibroplasia wrapping around junctional nests (Fig. 2.23). Bridging is the adhesion of nests from two separate adjacent rete ridges (Figs. 2.23 to 2.25). The dermoscopic features of dysplastic or Clark nevi often include a reticulated network with or without an atypia of the network often with granules distributed throughout the network (Fig. 2.26). Many pathologists who use the term dysplastic nevus tend to grade the lesions as either mild, moderate, and severe or low versus high grade. The authors of the most recent WHO classification of skin tumors advocate for a two-tiered grading of dysplastic nevi. Much of the grading is based on nuclear atypia. Atypia is graded as mild when the nuclei of lesional melanocytes are smaller or no more than equal in size to the nuclei of junctional keratinocytes. Moderate atypia indicates that the melanocyte nuclei are larger than keratinocyte nuclei but no more than twice as larger. A nuclear size difference of more than twofold is usually referred to as severe atypia. Not uncommonly, albeit more subjectively and less

A

reproducibly, architectural features are also taken into account for grading. Lesions with high cellular density and confluency of junctional melanocytes and/or focal suprabasilar melanocytes should be assigned a higher grade in spite of blander nuclear features (Fig. 2.27).25 Although criteria can be formulated and applied for grading dysplastic nevi, the clinical value of this effort remains to be determined. There is no good evidence that melanoma is more likely to develop in association with a dysplastic nevus with high-grade than low-grade atypia. However, as dysplastic nevi with higher levels of architectural disorder and atypia display more microscopic features overlapping with melanoma, it becomes more difficult to exclude melanoma, especially on a partial biopsy. Many pathologists who grade nevi use the grading as a surrogate for how concerned they are about the lesion and as a guide for when they think a nevus should be reexcised. However, instead of grading a dysplastic nevus, one may simply acknowledge diagnostic uncertainty, express worries about a possible melanoma in a comment, and provide this as a rationale to the clinician for reexcising an incompletely removed dysplastic nevus.

B Fig. 2.22  Lentiginous Compound Dysplastic Nevus. (A) Silhouette of the lesion displaying a broad junctional growth. (B) There is a junctional shoulder extending over several rete ridges beyond the intradermal nevus. Junctional nests vary in size and shape. There is focal bridging of nests.

A

B Fig. 2.23  Lamellar Fibroplasia. (A) Compound dysplastic nevus with focal confluency of melanocytes at the dermoepidermal junction. Nests vary in size, shape, and placement. Lesional melanocytes display enlarged nuclei. There is lamellar (onion skin–like) fibroplasia in the superficial dermis and an associated lymphocytic infiltrate with melanophages. (B) Dysplastic nevus with pigmented junctional nests surrounded by lamellar fibroplasia with underlying bandlike lymphocytic infiltrate.

CHAPTER 2  Acquired Melanocytic Nevi

A

B Fig. 2.24  Lentiginous Compound Dysplastic Nevus. (A) Solitary units and nests of melanocytes are present at the dermoepidermal junction of an epidermis, which displays lentigo-like hyperplasia and hyperpigmentation. A zone of lamellar fibrosis separates junctional melanocytes from intradermal melanocytes. (B) There is focal confluence of solitary units of melanocytes at the dermoepidermal junction. The nuclei of several melanocytes are larger than the nuclei of adjacent basilar keratinocytes.

A

B Fig. 2.25  Compound Dysplastic Nevus. (A) Junctional nests of melanocytes vary in size and shape. There is a junctional “shoulder.” There is inflammation and fibrosis separating aggregates of intradermal melanocytes. (B) Melanocytes are predominantly displayed as nests at the dermoepidermal junction. A zone of lamellar fibrosis separates junctional nests from intradermal melanocytes. Lymphocytes are associated with dermal melanocytes. Some of the melanocyte nuclei are enlarged and hyperchromatic.

A

B Fig. 2.26  Clinical Appearance of a Dysplastic Nevus. (A) Clinically, most dysplastic nevi that are greater than 6 mm in size have some border irregularity or multiple colors. The gross picture above shows a nevus measuring 6 mm with an irregular, notched border. (B) Dermoscopic assessment of dysplastic nevi may be very helpful in excluding melanoma. Despite the larger size and the presence of an irregular border, dermoscopically this lesion has a uniform reticulated network with symmetrically dispersed and uniformly pigmented granules.

19

20

SECTION I  Benign Cutaneous Melanocytic Proliferations

Because dysplastic nevi are uncommon on the face other than around the upper forehead and temples, one should hesitate to render a diagnosis of dysplastic nevus on a biopsy from the skin of the face, especially in an elderly individual or in association with solar elastosis. What at first glance may look like a possible dysplastic nevus may well be a melanoma.26 One of the challenges in determining the risk of a melanoma in a separate site from patients with dysplastic nevi is the discrepancy in defining the incidence of dysplastic nevi. The reported incidence is widely discrepant, varying from 2% to 50% of fair-skinned people. One study that examined dysplastic nevi from patients with and without melanoma was aimed at determining whether any features of the dysplastic nevus correlated with a history of a separate distinct melanoma

A

from the same patient.27 The diameter of the lesion was the only feature that had a statistically significant association with a personal history of melanoma. In addition, it has been shown that patients with many nevi including ordinary or dysplastic nevi have an elevated risk for melanoma.28,29 Hence two factors that do seem to reliably correlate with an increased risk of melanoma is the presence of many nevi (>100) and the larger size of nevi. Most dysplastic nevi display the features associated with this nevus variant throughout the entire lesion (Fig. 2.28). However, features of dysplastic nevi can also be combined with miscellaneous acquired or congenital nevi (Fig. 2.29). Some dysplastic nevi may display some spitzoid cytologic features.

B Fig. 2.27  (A) Junctional dysplastic nevus with proliferation of single melanocytes extending beyond rete ridges and filling the interretial space above the dermal papillae and focal suprabasilar melanocytes. (B) Cytologically the melanocytes show nuclear atypia with variably shaped and sized melanocytes.

B

A

C Fig. 2.28  Compound Dysplastic Nevus. (A) Clinical appearance: pigmented patch with irregular pigmentation and irregular borders. (B) Corresponding histology: broad plaquelike growth. (C) Junctional nests of variable size and shape are present overlying intradermal melanocytes. No pagetoid melanocytes are present. A few melanocyte nuclei are slightly enlarged.

CHAPTER 2  Acquired Melanocytic Nevi

A

B

C

D

E Fig. 2.29  Combined Ordinary and Dysplastic or Clark Nevus. (A) Clinical appearance: a pigmented papule is associated with a lightly pigmented patch. (B) Corresponding histopathology: the ordinary nevus is flanked by a junctional shoulder. (C) Small junctional nests. (D) The melanocytes in some nests are slightly enlarged and hyperchromatic. There is associated inflammation.

21

22

SECTION I  Benign Cutaneous Melanocytic Proliferations

DIFFERENTIAL DIAGNOSIS Melanocytic Nevus With Atypical Features Versus Melanoma In Situ Associated With a Nevus Melanoma may arise in association with a melanocytic nevus. In most cases of melanoma associated with an acquired melanocytic nevus, melanoma begins to develop in the epidermis (melanoma in situ). Although a well-developed melanoma in situ is readily distinguished from the associated nevus remnant by its growth pattern and cytology, early evolving lesions can be difficult to distinguish from a melanocytic nevus with atypical features. In many cases the first microscopic clue to the presence of melanoma in situ is the asymmetry of a lesion’s silhouette at scanning magnification. The second is poor lateral circumscription of intraepidermal melanocytes. Usually, melanoma in situ is characterized by a predominance of solitary units of melanocytes and/or presence of melanocytes at all layers of the epidermis (Fig. 2.30). Florid pagetoid spread is a strong indicator for the presence of melanoma in situ. However, caution is necessary not to mistake any pagetoid spread as evidence for melanoma. Focal pagetoid spread, for example, can be seen in many nevi, including dysplastic nevi, after trauma. Some lesions of melanoma in situ lack significant pagetoid spread and display predominantly a lentiginous junctional growth pattern (Fig. 2.31). Because “atypical” melanocytic nevi may also display architectural disorder, atypia, and some asymmetry and are sometimes associated with less well-defined borders, the distinction of an atypical nevus from melanoma in situ associated with a nevus can at times be very difficult or, especially on a partial biopsy, when the entire silhouette of the lesion is not available for review, impossible. In such cases, it is best to acknowledge that melanoma in situ cannot be excluded and to recommend a reexcision.

Fig. 2.30  Pagetoid melanoma in situ associated with a melanocytic nevus.

A

Dysplastic Nevus Versus Melanoma Melanoma may arise in association with any acquired nevus, including a dysplastic nevus (Figs. 2.32) or simulate the appearance of a dysplastic nevus (Figs. 2.33 to 2.35) or any other acquired nevus. Most dysplastic nevi can reliably be distinguished from melanoma. In nevi the predominant architecture is nested and there is usually good lateral circumscription, orderly growth, and some level of symmetry. The degree of lentiginous growth of single cells is limited. In some nevi, one may see contiguous single cells extending from rete to rete and filling some of the interreteal spaces, but typically the confluent junctional area is limited to the span of a few rete. Suprabasal presence of melanocytes is limited to a few cells often around a hair follicle ostium. The epidermal contour is mostly intact. Features favoring melanoma include predominance of single cells, asymmetry and poor lateral circumscription, broad zones of lentiginous single cell growth, and prominent pagetosis. Consumption of the epidermis with loss of rete ridges also raises the suspicion for melanoma. More than just random cells with high-grade nuclear atypia is another concerning feature. The more of these features seen in a given melanocytic neoplasm, the greater the likelihood of a diagnosis of melanoma. In some cases, in which the distinction between a severely dysplastic nevus and melanoma is very difficult, deeper sections to assess for the presence of additional histologic criteria may be helpful. Melanomas not uncommonly display only some of the expected features. For example, lesional melanocytes may display high-grade nuclear atypia but maintain a predominantly nested architecture, or, conversely, some melanomas may not have high-grade nuclear atypia

B

C Fig. 2.31  Lentiginous Melanoma In Situ Arising in Association With a Compound Nevus. (A) Silhouette of the lesion (hematoxylin and eosin stain [H&E]). (B) An immunostain for Melan-A highlights broad lentiginous junctional growth of melanocytes, which contributes to an asymmetric silhouette. (C) Confluency of junctional melanocytes with nuclear atypia.

CHAPTER 2  Acquired Melanocytic Nevi

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A

Fig. 2.33  Dysplastic Nevus-Like Melanoma. Compound melanocytic proliferation with complex growth. Expansile dermal nests have pushed down solar elastotic material to the deeper dermis. Cytogenetic analysis of this lesion revealed clonal segmental gains in 11q13 throughout the lesion.

B Fig. 2.32  (A) Melanoma associated with a dysplastic nevus. (B) Juxtaposition of ulcerated melanoma nodule lacking maturation and adjacent dysplastic nevus.

A B

C

D Fig. 2.34  Melanoma. (A) Nevoid silhouette with a predominant nested pattern. (B) A few pagetoid melanocytes can be seen. (C) The nested dermal melanocytes are enlarged and hyperchromatic. (D) The dermoscopic findings document an atypical or irregular pigment network, irregular streaks and pseudopods, irregular black blotches, and a blue/gray veil—features diagnostic for melanoma. Fluorescence in situ hybridization assessment with the green-colored probe targeting CCND1 at 11q13 shows copy number gains of CCND1. Thus correlation with dermoscopic and molecular findings favors a diagnosis of melanoma over that of an atypical nevus.

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SECTION I  Benign Cutaneous Melanocytic Proliferations

B

A

Fig. 2.35  Melanoma Without Pagetoid Spread. (A) Clinical findings: The lesion grew from 3 to 5 mm in diameter within a period of 3 months (a, the dermoscopic image and b, gross clinical image of the lesion). (B) There is no pagetoid melanocytic growth, but complex growth pattern at the dermoepidermal junction with severe nuclear atypia and limited maturation. Fluorescence in situ hybridization studies revealed gains at 11q13 (CCND1).

but may have asymmetric and poorly circumscribed broad and irregular junctional growth, which is diagnostic of melanoma. Most of the criteria for a severely dysplastic nevus are the same as those used for early melanoma, with the exception that in a severely dysplastic nevus the morphologic feature of concern is focal rather than widespread. These cases may be difficult to differentiate from melanoma arising focally within a nevus in which the atypia may also be focal. Ancillary dermoscopy (immunohistochemical, cytogenetic, or other studies) may be helpful in such cases. Hence one must pay attention to all details and use as many clues as possible, including clinical, dermoscopic, and test results from ancillary studies when a definitive diagnosis cannot be made with confidence by microscopic review alone.

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