Melanocytic Proliferations

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Melanocytic Proliferations Klaus J. Busam

The histologic interpretation of pigmented lesions represents one of the most common and at times most difficult challenges in dermatopathology. This chapter introduces the reader to basic aspects in the histologic diagnosis of melanocytic lesions.

LENTIGINES AND LENTIGO–LIKE LESIONS SOLAR LENTIGO CliniCal Findings The solar lentigo is a usually circumscribed pigmented macule ranging in color from tan to dark brown. It typically occurs on sun-exposed skin of older individuals (Fig. 12-1, A). In contrast with freckles, solar lentigines persist in the absence of sunlight. Solar lentigines are often multiple. They may become confluent and large, and clinically simulate a lentigo maligna.

HistologiC Features The solar lentigo shows hypermelaninization of basilar keratinocytes, which is most pronounced at the tips of often elongated, club-shaped rete ridges (Fig. 12-1, B). A slight increase in the frequency of cytologically bland basilar melanocytes is not uncommon. There may be hyperkeratosis. On occasion, particularly in the face, epidermal rete ridges may be short or effaced. Solar lentigines may be associated with a lymphocytic, often lichenoid inflammatory reaction, with scattered Civatte bodies and/or melanophages in the superficial dermis.

diFFerential diagnosis The main diagnostic issues are the distinction of a melanocytic proliferation from a pigmented keratosis (macular

seborrheic, lichen planus-like keratosis, or pigmented actinic keratosis) and the classification of the melanocytic proliferation as benign or malignant. Solar lentigo may coexist with or transition into a keratosis, in particular a reticulated seborrheic keratosis or lichen planus-like keratosis. The keratoses differ from solar lentigo by epidermal hyperplasia and hyperkeratosis. Solar lentigo differs from actinic keratosis by the lack of basilar (or suprabasilar) keratinocytic atypia (e.g., hyperchromatic nuclei). Benign melanocytic proliferations that may be confused with a solar lentigo include lentigo simplex and pauci-cellular lentiginous junctional nevus (aka “jentigo”). A lentigo simplex differs from solar lentigo by a definite increase in the density of solitary units of melanocytes within the lesion. The diagnosis of a junctional nevus requires identification of a junctional nest (group of three or more melanocytes). Solar lentigo may also at times be difficult to distinguish from a histologically subtle early evolving melanoma in situ of lentigo maligna type, especially if the solar lentigo occurs in the setting of background melanocytic hyperplasia of chronically sun-damaged skin. Clinical correlation (knowledge of the size and complexity of the lesion) is paramount in such cases to arrive at the correct diagnosis. Sampling errors may pose a pitfall. The clinician may have taken the biopsy from a paucicellular focus of an otherwise more cellular melanocytic lesion. Furthermore, the cellular density may vary within a biopsy. Multiple levels and immunostains for melanocytic differentiation markers may be necessary to document a histologically subtle melanocytic proliferation, especially if the dermal-epidermal junction is blurred by a lichenoid inflammatory reaction. Knowledge of the clinical features of the lesion (size, complexity) greatly facilitates interpretation of histologically subtle alterations.

LENTIGO SIMPLEX CliniCal Findings A lentigo simplex (also called a nevoid lentigo) is a well-circumscribed pigmented macule. It is usually small (a few millimeters in diameter) and may occur 437

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LentiginouS MeLAnocytic ProLiFerAtionS Solar lentigo

Lentigo simplex

Lentiginous nevus

Lentiginous melanoma in situ

Size

Small (< 4mm)

Small (< 4 mm)

Variable

Variable, often large

Borders

regular

regular

regular

Irregular

Density of mC

Normal or slightly increased

Slightly increased

Increased

Significantly increased

Confluence of mC

absent

absent

may be present

Common

melanocytic nests

absent

absent

present

Common

pagetoid mC

absent

absent

absent

Common

Solitary units of mC along adnexa

absent

absent

rare

Common

atypia of mC

rare

rare

rare

Common Common

multinucleated melanocytes absent

absent

rare

Skip areas

absent

absent

Usually absent

Common

epidermal rete ridges

Normal or slightly elongated

Normal or slightly elongated

Normal or elongated

Normal or effaced

mc, melanocyte.

A

B

Figure 12-1 Solar lentigo. A, Clinically a slightly irregular brown macule is present. B, histologically slightly elongated rete ridges show basal layer hyperpigmentation. there is associated solar elastosis.

anywhere on the body’s surface. It is likely that some of these lesions represent the earliest stage in the evolution of lentiginous melanocytic nevi. Pigmented lesions with a lentigo simplex–like histologic picture occurring at mucosal or paramucosal sites have also been termed labial and genital melanotic macules (Fig. 12-2, A). Genital lentigines are often associated with stromal melanophages. A lentigo–like lesion may be the histologic substrate of benign melanonychia striata, Psoralen and UVA treatment-induced hyperpigmentation, or may be seen in the epidermis overlying a dermal scar or dermatofibroma. Various clinical scenarios have been described in which multiple lentigines can occur. In Carney’s complex, for example, multiple lentigines and blue nevi are

seen in association with melanotic schwannoma, myxomas, and endocrine disorders. Lentigines have also been described in Peutz-Jeghers syndrome, in patients with familial gastrointestinal stromal tumors, and as part of a paraneoplastic phenomenon (Peutz-Jeghers–like pigmented macules, usually in association with esophageal or intestinal adenocarcinomas).

HistologiC Features Lentigo simplex is histologically characterized by hyperpigmentation of basilar keratinocytes and an increase in the density of solitary units of melanocytes at the

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SyndroMeS With LentigineS name

Features

laugier-hunziker syndrome

melanonychia, mucosal and cutaneous lentigines; sporadic; not associated hamartoma or malignant tumor

peutz-Jeghers syndrome

mucosal (mostly oral, labial) and cutaneous lentigines; hamartomatous gastrointestinal polyps autosomal dominant; mutation in StK11/ lKB1 gene

Carney complex

1. Cardiocutaneous type, also called lamB syndrome (Lentigines, atrial myxomas, mucocutaneous myxomas, blue nevi) 2. multiple endocrine neoplasia type pigmented nodular adrenocortical disease; pituitary adenoma; gonadal, thyroid tumors and schwannomas autosomal dominant; mutation in pKar1a gene

leopard syndrome

Lentigines eCg abnormality ocular hypertelorism Pulmonic stenosis Abnormality of genitalia retarded growth, skeletal abnormalities deafness autosomal dominant; mutation in ptpN11 gene

dermal-epidermal junction confined to the clinical correlate of a small and circumscribed macule (Fig. 12-2, B). The melanocytes usually lack cytologic atypia. The nucleus of a melanocyte is usually smaller in diameter than the nucleus of a keratinocyte. On occasion the

melanocytes and their nuclei may be large and have an epithelioid appearance (Spitzoid lentigo). The presence of enlarged cells per se; that is, without an increase in cell density, should not lead to concern about melanoma or surgical intervention. Epidermal hyperplasia with elongation of rete ridges may be an associated histologic feature of lentigines. Some lesions show marked melanin pigment deposition in keratinocytes, melanocytes, and/ or superficial dermal macrophages and may represent a histologic correlate to what is clinically perceived as “ink spot” lentigo.

diFFerential diagnosis Lentigines need to be distinguished from solar lentigo, lentiginous nevi, including nevus spilus, but most importantly from in situ melanoma. A solar lentigo shares with a lentigo simplex the feature of hyperpigmentation of basilar keratinocytes. However, in contrast with a simple lentigo, a solar lentigo lacks an associated distinct increase in the cellular density of basilar melanocytes. Small lentiginous junctional melanocytic nevi may have only very few nests. Step sections may be necessary to reveal such nests and allow distinction of such nevi from a simple lentigo.

MISCELLANEOUS MELANOTIC MACULES Hypermelanosis of basilar keratinocytes can be seen in a number of other lesions, such as Becker’s nevus (hyperpigmentation associated with hypertrichosis and smooth

B A

Figure 12-2 Lentigo simplex. A, Clinically a small dark brown macule is present. B, histologically the epidermal rete ridges are slightly elongated, associated with basal layer hyperpigmentation as well as a slight increase in the number of cytologically bland intraepidermal melanocytes.

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tomic (e.g., junctional, compound, dermal) attributes or by eponyms (e.g., Spitz’s, Unna’s, Clark’s). A detailed discussion of various terms and classifications is beyond the scope of this chapter. The main issue regarding the diagnosis of melanocytic nevi is their distinction from melanoma. Recognizing variants of melanocytic nevi and familiarity with their spectrum of histologic appearances (e.g., pagetoid Spitz’s nevus, acral nevus, recurrent nevus) serves to avoid confusion with melanoma. Recently it has also become apparent that distinct molecular alterations are associated with different types of melanocytic nevi. Although BRAF mutations are frequently found in acquired nevi, including dysplastic nevi, N-RAS mutations are common in congenital nevi. Figure 12-3 Becker’s nevus. there is unilateral hyperpigmentation and hypertrichosis of the left shoulder region.

muscle hamartoma) (Fig. 12-3), melasma, the pigmented macules of Albright’s syndrome (associated with fibrous dysplasia and endocrinopathy), and café-au-lait macules.

MELANOcyTIc NEvI Melanocytic nevi are benign proliferations of melanocytes. Historically they have been classified by various clinical (e.g., congenital, acquired, blue) or microana-

cLASSiFicAtion oF MeLAnocytic nevi clinical criteria age of onset: Congenital or acquired anatomic site: acral, genital, conjunctival, other

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histologic Parameters microanatomic involvement Junctional (intraepidermal only) Compound (dermal and intraepidermal) Dermal (intradermal only) Cell type: e.g., spindle and epithelioid cell nevus, pigmented spindle cell nevus » eponyms (selected examples) » Unna’s nevus (ordinary melanocytic nevus) » Miescher’s nevus (ordinary melanocytic nevus) » Clark’s nevus (overlaps with dysplastic nevus) » Spitz’s nevus (spindle and epithelioid cell nevus) » Zitelli’s nevus (superficial congenital nevus) » Mark’s nevus (superficial and deep congenital nevus) » Myerson’s nevus (nevus with eczematous epidermal changes) » Tieche’s nevus (common blue nevus) » Ota’s nevus (nevus fuscoceruleus ophthalmomaxillaris) » Ito’s nevus (nevus fuscoceruleus acromiodeltoideus) » Sun’s nevus (nevus fuscoceruleus zygomaticus)

COMMON (TYPICAL/ORDINARY) ACQUIRED MELANOCYTIC NEVI CliniCal Findings Melanocytic nevi tend to be symmetric and have fairly sharp borders. They may be flat (Fig. 12-4) or raised (Fig. 12-5). Their color may be identical to the surrounding skin or differ from it (varying from pink or red to light or dark brown).

HistologiC Features Common or ordinary nevi are symmetric and circumscribed (Fig. 12-6). The melanocytes may populate the epidermis as nests only along the dermal-epidermal junction (junctional nevus) (Fig. 12-7), as well as in the dermis (compound nevus) (Fig. 12-8), or be confined to

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Figure 12-4 Junctional melanocytic nevus. a circumscribed flat uniform brown macule is present.

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coMMon Acquired MeLAnocytic nevuS clinical Findings Usually small Circumscribed and symmetric; flat or raised Variable colors (pink, tan, brown), but usually uniform within a lesion

» » »

Figure 12-5 compound melanocytic nevus. a brown nodule is present.

the dermis without involvement of the overlying epidermis (intradermal melanocytic nevus). In ordinary junctional and compound nevi, nests predominate at the dermal-epidermal junction and are preferentially positioned at or near the tips of rete ridges (Fig. 12-9). Nevomelanocytes may be heavily pigmented or lack melanin granules by light microscopy. Melanocytic nevi may be associated with epidermal hyperplasia, which at times may have features of a keratosis (keratotic nevus). A melanocytic nevus may also incidentally collide with a seborrheic keratosis. Compound and dermal nevi typically show zonation with depth (so-called maturation) in the dermis. Such maturation may be manifest at the level of individual cells. Large epithelioid (type A) melanocytes tend to dominate in the superficial dermis (Fig. 12-10, A). With

A

histologic Features Usually small circumscribed and symmetric Junctional melanocytic proliferation, if present: predominant nested pattern, rare solitary units of melanocytes most melanocytic nests are at tips of rete ridges Dermal nevus component evidence of maturation often “orderly” nested growth pattern often symmetric wedge or plaque-like growth pattern lack of marked atypia and mitoses possible associated features: » epidermal hyperplasia with hyperkeratosis (keratotic nevus) » papillomatous epidermal hyperplasia (papillomatous nevus) » Balloon cell changes (balloon cell nevus) » Inflammation and regression (e.g., halo nevus) » Fatty metaplasia of the dermal stroma » many others (e.g., calcifications, oncocytic changes, etc.)

» » » » » » » » » »

descent into the reticular dermis, melanocytes tend to have less cytoplasm (type B cells) (see Fig. 12-10, A) and not infrequently become fusiform (type C cells) at the base of a lesion (Fig. 12-10, C). The full range of cytologic appearances from type A to type C melanocytes is seen only in a minority of nevi. Some nevi may be entirely epithelioid. Others may be entirely fusiform with prominent neural/schwannian differentiation (neuronevus or neurotized nevus) (Fig. 12-11). Neurotized nevi may show structures reminiscent of Wagner-Meissner corpuscles.

B

Figure 12-6 Silhouette of an ordinary melanocytic nevus. A, Symmetric silhouette of an ordinary polypoid melanocytic nevus. B, Symmetric silhouette of an ordinary plaquelike melanocytic nevus.

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Figure 12-7 Junctional melanocytic nevus. Nests of melanocytes are present at the dermal-epidermal junction.

Figure 12-8 compound melanocytic nevus. melanocytes are present at the dermal-epidermal junction and in the superficial dermis.

Zonal changes are not restricted to cell size and shape. The growth pattern of the melanocytes and their degree of pigmentation often changes with microanatomic depth. Superficially nests tend to be larger. With descent into the reticular dermis, they usually become smaller. At times melanocytes at the base of a nevus are dispersed as solitary units in the stroma. Intracellular melanin pigment tends to be more prominent in the superficial portion of a nevus than in its deep component (Fig. 12-12). Exceptions to typical zonation exist (e.g., inverted type A nevus, with large pigmented epithelioid melanocytes in the mid or deep dermis; see the following). Mitoses are typically absent in common nevi. However, rare mitoses, especially in the superficial portion of a nevus, may occur. Several mitoses may be seen

Dermatopathology

Figure 12-9 Junctional melanocytic nevus. Nests are positioned at the tips of rete ridges. Nests predominate.

in benign growing nevi during pregnancy or in congenital nevi. Nevi may rarely be ulcerated. This is usually secondary to trauma/excoriation. Some dermal nevi are inflamed and/or may show features of regression (loss of melanocytes associated with various stromal changes, such as edema, fibrosis, hypervascularity, presence of melanophages). Inflammation is usually sparse, but may be dense. Inflammation and/or regression at the periphery of a nevus may lead to a clinically depigmented or erythematous rim around a pigmented center (Fig. 12-13). Such nevi are referred to as “halo nevi.” A halo phenomenon may occur in other types of nevi, such as dysplastic or Spitz’s nevi. Another pattern of inflammatory process that may be found in association with a melanocytic nevus is that of spongiotic dermatitis. A melanocytic nevus with features of eczema is called a Myerson’s nevus. Various peculiar cytologic changes of melanocytes may occur in common as well as any other type of nevus, such as clear cell/balloon cell, oncocytic features, or prominent multinucleation, including Touton-type giant cell formation. Nevi may show fatty metaplasia (Fig. 12-14) or may be associated with calcifications. In some nevi, there is prominent cellular dyscohesion leading to the formation of “pseudovascular” spaces (Fig. 12-15).

diFFerential diagnosis Confusion of common nevi with melanoma is usually not a problem, except for rare cases of so-called nevoid melanoma (see the following). Dermal melanocytic nevi may be associated with an increase in the cellular density

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A

B

C

Figure 12-10 “Maturation” of a melanocytic nevus. A, type a melanocytes are large epithelioid cells. B, type B melanocytes are small epithelioid cells with little cytoplasm. c, type C melanocytes are fusiform cells with schwannian features.

of solitary units of melanocytes in the overlying epidermis, a finding that may raise concern about possible in situ melanoma, especially on a small shave biopsy taken from sun-damaged skin of the face. If the increase in number of intraepidermal melanocytes is limited to a

small area of the center of the lesion, it is in keeping with a benign nevus. If it is diffuse and extends to biopsy edges, an additional biopsy may be necessary to distinguish in situ melanoma from melanocytic hyperplasia. In situ melanoma can be diagnosed with confidence,

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B

A

C

D

Figure 12-11 neuronevus. A, Silhouette of a compound melanocytic nevus with “neurotization” of its dermal component. B, Superficially a mixture of nests of small epithelioid melanocytes and diffuse arrangement of fusiform melanocytes with schwannian features is seen. c, only the epithelioid melanocytes are immunoreactive for melan-a. the fusiform melanocytes are negative. d, Neuroid structures are present.

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Figure 12-12 Pigmented melanocytic nevus. melanin pigment is typically more prominent in the superficial portion of a nevus.

Figure 12-14 Melanocytic nevus with fatty changes. adipocytes are present in association with a dermal melanocytic nevus.

if pagetoid spread of melanocytes is prominent, melanocytes become confluent as solitary units, and/or an atypical lentiginous melanocytic proliferation extends beyond the periphery of the nevus. Extensive ulceration may also pose a problem because it precludes evaluation of the part of the lesion that has

been removed by trauma. Mitotic figures in dermal melanocytes underneath an ulcer should not be dismissed as being reactive, but viewed as a red flag for possible melanoma and should prompt further careful examination of a lesion for other clues that may suggest melanoma.

B A

Figure 12-13 “halo” phenomenon. A, Clinically a brown macule is surrounded by a hypopigmented rim. B, histologically the nevomelanocytes (stained immunohistochemically for melan-a) are associated with a dense lymphocytic infiltrate.

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Figure 12-15 Pseudovascular changes of a melanocytic nevus. artifactual clefts are lined by melanocytes.

Amelanotic melanocytic nevi may also be confused with various benign nonmelanocytic proliferations, such as neurofibromas, cellular neurothekeomas or histiocytomas, such as juvenile xanthogranuloma. The latter two are easily distinguished from nevi by immunohistochemistry. Cellular neurothekeomas negative for S-100 protein histiocytomas are negative for melanocyte differentiation markers (e.g., melan-A, tyrosinase). The distinction of a neurofibroma from a completely neurotized neurofibroma–like nevus can be very difficult. The presence of rare epithelioid cells and/or small nests indicates a melanocytic nevus (see Fig. 12-11, B). Any immunoreactivity for melanocyte differentiation markers also favors a nevus, except for pigmented neurofibromas.

Dermatopathology

type is a fairly common clinical finding (5% to 15% of the population). However, precise statistical data are problematic in this regard because of interobserver variation in the criteria used for classifying nevi as dysplastic or atypical. Some pathologists view the DMN not only as a marker of risk for melanoma in the context of the dysplastic nevus syndrome, but also as a biologically “intermediate” lesion (manifestation of tumor progression) in the spectrum from banal nevi to melanoma. Conflicting results and opinions about the significance of dysplastic nevi can in part be traced to variable definitions of the term. Most pathologists who use the term dysplastic nevus require both a certain set of architectural features as well as cytologic alterations for its diagnosis (see the following). Others, who tend to prefer the term Clark’s nevus, pay attention primarily to architectural features. The latter approach has been criticized by advocates of the term dysplastic nevus with the argument that, if cytologic atypia is not required for the diagnosis, the definition of the term becomes too broad resulting in inclusion of many ordinary nevi, which commonly show a minor element of architectural disorder. Irrespective of the terminology, the DMN is essentially a variant of a benign acquired melanocytic nevus with features as outlined in the following.

CliniCal Findings Clinically dysplastic nevi tend to be larger than ordinary nevi and measure usually more than 4 mm in diameter (see Figs. 12-16 and 12-17). They often show variation in color (mixture of tan, brown, pink) and have a slightly irregular or “fuzzy” periphery.

DYSPLASTIC MELANOCYTIC NEVI The concept and definition of the dysplastic melanocytic nevus (DMN; also called melanocytic nevus with architectural disorder and atypia) remain controversial. A detailed discussion of this controversy is beyond the scope of this chapter. A few comments, however, are necessary. This type of nevus was first described in context of the so-called B-K mole or atypical mole syndrome, which was later termed dysplastic nevus syndrome. The syndrome describes individuals at increased risk for melanoma with a skin phenotype characterized by the presence of numerous nevi, many of which are larger and more irregular than most ordinarily acquired nevi (Fig. 12-16). It was then recognized that such nevi also occur as solitary lesions or may be present in small numbers (Fig. 12-17). As such this nevus

Figure 12-16 dysplastic nevus syndrome. a patient with numerous clinically irregular melanocytic nevi.

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dySPLAStic MeLAnocytic nevuS clinical Findings Usually larger than most ordinary nevi Irregular borders and/or colors (not up to the level of melanoma)

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histologic Features architectural disorder Slight asymmetry Slightly irregular border Focal single cell proliferation of melanocytes along and in between rete ridges » Variation in size and shapes of nests » Bridging/fusion of nests » Shoulder phenomenon

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Figure 12-17 dysplastic nevus. pigmented lesion with fuzzy borders and variations in colors and texture.

HistologiC Features Dysplastic nevi display both “architectural disorder and cytologic atypia” of melanocytes (Fig. 12-18). Frequently there are associated stromal changes. Architectural disorder refers to the deviation of the growth pattern of melanocytes from an idealized prototypical “ordinary” nevus. It includes slight asymmetry, a lentiginous proliferation of solitary units of melanocytes along and focally in between elongated rete ridges, variation in the size and placement of junctional nests with fusion/bridging of nests (Figs. 12-18 and 12-19), and/or an irregular peripheral border, including a shoulder phenomenon (extension of the junctional melanocytic proliferation of a compound melanocytic nevus beyond the periphery of its dermal component) (Fig. 12-20). Cytologic atypia refers to nuclear alterations, such as nuclear enlargement,

Figure 12-18 dysplastic nevus. Bridging and fusion of junctional nests of atypical melanocytes are apparent. there is associated dermal fibrosis and inflammation.

cytologic Atypia enlarged nuclei hyperchromatic nuclei Distinct nucleoli Stromal changes lamellar fibrosis Inflammation

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hyperchromasia, and/or the presence of prominent nucleoli (see Figs. 12-18 and 12-19). Stromal changes typically associated with dysplastic nevi include lymphocytic infiltrates, hypervascularity, and/or fibroplasia of the superficial dermis, which often shows a lamellar pattern (Fig. 12-21). Naturally there is a spectrum in the extent of such alterations. Some pathologists have attempted to grade the degree of cytologic atypia from mild to severe. Atypia is judged as mild if the nuclei of melanocytes are slightly hyperchromatic, but overall similar in size to the nuclei of keratinocytes. A one- to twofold enlargement, often

Figure 12-19 dysplastic nevus. there is architectural disorder (fusion of nests, confluence of single cells along the dermal-epidermal junction) and atypia (melanocytes with enlarged and hyperchromatic nuclei).

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Figure 12-20 “Shoulder phenomenon.” the junctional melanocytic proliferation extends beyond the periphery of the dermal melanocytic nevus component.

Figure 12-21 Stromal changes associated with a dysplastic nevus. there is marked lamellar fibrosis in the superficial dermis.

accompanied by other nuclear irregularities (irregular contours, nucleoli, hyperchromatism), is judged as moderate. A more than twofold increase in nuclear size associated with marked hyperchromatism or prominent nucleoli qualifies as severe atypia. Dysplastic nevi with moderate or severe atypia have also been referred to as high-grade lesions, whereas those with only slight atypia are judged as low-grade lesions. The rationale behind grading dysplastic nevi is an attempt to separate slightly irregular, but essentially banal nevi from those that might be confused with melanoma, that are possibly more likely to progress to melanoma, or that may be associated with a higher risk for melanoma. However, much of this exercise is currently still speculative, controversial and of unproven benefit for patients. A practical value of grading a DMN may be

Dermatopathology

that it confers to the dermatologist some information about the pathologist’s concern about the lesion (because of some histologic overlap with melanoma), which may influence the need for obtaining a second opinion and/ or the decision to perform a complete excision or not. A melanocytic proliferation diagnosed as severely atypical or dysplastic by one pathologist may represent an in situ melanoma to the eye of another. A melanocytic nevus with only mild atypia is less likely to be diagnosed as melanoma by another pathologist. However, instead of using a formal grading scheme, a pathologist may prefer to express his or her concerns about a pigmented lesion to the clinician in different ways and simply state that the histologic features overlap with early melanoma, and therefore recommend complete surgical excision.

diFFerential diagnosis The only distinction that really matters, of course, is the one between melanoma and nevus. Melanomas generally are more asymmetric and less circumscribed than dysplastic nevi. They show a more complex growth pattern along the dermal-epidermal junction with a greater distortion of the epidermis (loss of rete ridges or consumption of the epidermis). Pagetoid spread of intraepidermal melanocytes greatly facilitates the recognition of in situ melanoma. However, its presence is not entirely specific for melanoma. Focal pagetoid spread may occur in nevi, including dysplastic nevi, usually in the center of the lesion or in association with features of trauma. Prominent and/or chaotic pagetoid spread or pagetoid melanocytes at the periphery of a lesion indicates the presence of in situ melanoma. In contrast with the majority of melanomas, the dermal component of a DMN shows evidence of maturation. Because the features of the DMN overlap with melanoma and melanoma may be associated with a DMN, it may not be possible on a small partial biopsy to make a reliable distinction between a DMN and melanoma, because some parameters cannot be evaluated (overall symmetry, features of the borders of the lesion). In such cases it is best to defer the final diagnosis to the review of the completely excised lesion.

SPINDLE AND/OR EPITHELIOID MELANOCYTIC (SPITZ’S) NEVI CliniCal Findings Spitz’s nevi preferentially affect the face and lower extremities of children and adolescents, but may occur anywhere, as well as in adults. Often they appear as red,

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SPindLe And ePitheLioid ceLL. MeLAnocytic (SPitZ’S) nevuS clinical Findings » Usually children and young adults » typical manifestation: pink papule on face or extremities Architecture Symmetric (often wedge shaped) Sharp peripheral borders Variation in size and shape of densely cellular nests pagetoid melanocytes may be present focally

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cytology large spindle and epithelioid cells with abundant pink cytoplasm evidence of maturation rare dermal mitoses are acceptable, if present in the superficial or mid portion of the lesion » Secondary epidermal or stromal changes » Dull pink globules (Kamino bodies) present in many but not all cases » Vascular ectasia and edema » patchy lymphocytic aggregates » epidermal hyperplasia may be prominent

» » » Figure 12-22 Spitz’s nevus. a circumscribed dome-shaped red papule is present.

pink, or flesh-colored dome-shaped papules (Fig. 12-22). Flat, pigmented, and fibrosing variants exist. Clinically Spitz’s nevi may be confused with nonmelanocytic lesions, such as angiomas, pyogenic granulomas, fibromas, or adnexal tumors.

HistologiC Features The hallmark of Spitz’s nevi is their composition of large plump spindle and epithelioid melanocytes (Fig. 12-23). Like other benign melanocytic nevi, they are typically sharply circumscribed, display a symmetric growth pattern, and show evidence of maturation. Compound and dermal Spitz’s nevi are usually wedge shaped. Common associated secondary features are epidermal hyperplasia, dull pink globules (Kamino bodies) (Fig. 12-24) at the dermal-epidermal junction, stromal edema, and vascular ectasia. Scattered lymphocytic aggregates may be present. There is a spectrum of cytologic features from large epithelioid to spindle cells. Some lesions are predominantly epithelioid. Others may preferentially contain spindle cells. In many junctional or compound Spitz’s nevi, fascicles of spindle cells are arranged in tight fascicles parallel to epidermal rete ridges in a pattern that has been likened to hanging bananas (Fig. 12-25). Junctional nests of melanocytes often show “clefts” (see Fig. 12-25). Mitoses may be found, but are usually rare and limited to the superficial portion of densely cellular lesions. Sclerosing variants of Spitz’s nevus exist. Most of them are dermal nevi, in which pleomorphic epithelioid melanocytes are dispersed as small nests, fascicles, and single cells in a densely fibrous stroma (Fig. 12-26). There is often association with epidermal hyperplasia. At scanning magnification, these variants may resemble a dermatofibroma.

Figure 12-23 Junctional Spitz’s nevus. Nests of large plump spindle and epithelioid melanocytes are present with clefts surrounding junctional nests. Dull pink globules (“Kamino” bodies) are also identified.

Many Spitz’s nevi are amelanotic or paucimelanotic. However, heavily pigmented variants thereof exist with various proportions of spindle to epithelioid melanocytes. The so-called pigmented spindle cell nevus represents one pole of the spectrum of such pigmented nevi (Fig. 12-27, A). It is histologically characterized by a predominant composition of heavily pigmented slender fusiform melanocytes (Fig. 12-27, B,C). The lesions are usually small, symmetric, and sharply circumscribed. There are typically densely cellular nests at the

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Figure 12-24 compound Spitz’s nevus. Fascicles of spindle and epithelioid melanocytes are present in association with epidermal hyperplasia and dull pink globules at the dermal-epidermal junction.

dermal-epidermal junction. The epidermal rete ridges tend to be hyperplastic. Melanin pigment is often present in the cytoplasm of keratinocytes at all layers of the epidermis, including the stratum granulosum and corneum (not to be confused with melanocytes). Rare pagetoid melanocytes may be found, especially in the center

A

Figure 12-26 Sclerosing Spitz’s nevus. A, Wedge-shaped intradermal melanocytic nevus. B, plump spindle and epithelioid cells, some with nuclear atypia, are embedded in fibrotic dermis.

Figure 12-25 Spitz’s nevus. Fascicles of fusiform melanocytes are present in association with elongated rete ridges.

B

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B A

C

Figure 12-27 Pigmented Spitz’s nevus. A, a small dark circumscribed melanocytic nevus is seen. B, histologically, it is composed of many nests of melanocytes at the dermal-epidermal junction surrounded by clefts, and associated with epidermal hyperplasia and hyperpigmentation. c, the nests are composed of slender pigmented fusiform melanocytes.

of the lesion. Dull pink globules (Kamino bodies) are frequently seen. The superficial dermis usually contains many melanophages.

diFFerential diagnosis There is a body of literature on the difficulty of distinguishing atypical or unusual variants of Spitz’s nevi from Spitz’s nevus–like melanomas. This is reflected in diagnostic controversies, ambiguous terms, such as borderline or minimally deviant, and misdiagnoses. For the differential diagnosis between Spitz’s nevus and Spitzoid melanoma, the following features favor melanoma: large size, asymmetry, complex growth pattern, presence of mitotic figures in deep dermal melanocytes, atypical mitotic figures, thinned epidermis with effaced rete ridges, lack of maturation, and absence of Kamino bodies. However, none of these features is specific for melanoma. Each of them can also be seen in nevi. Likewise features more often found in Spitz’s

nevi than melanoma, such as Kamino bodies, may also be present in fully malignant tumors. However, melanomas tend to show only rare and small Kamino bodies. Numerous large Kamino bodies strongly favor a benign lesion. In distinguishing a Spitz’s nevus from melanoma, it is important to realize that some pagetoid spread of melanocytes is acceptable for the diagnosis of a nevus so long as the other features of the lesion favor a benign melanocytic proliferation. Pagetoid spread of melanocytes in Spitz’s nevi is usually focal, at or near the center of the lesion, and often associated with ascent of melanocytic nests rather than only solitary units. Pagetoid spread is prominent on rare occasion (pagetoid Spitz’s nevus) (Fig. 12-28). However, this variant is rare and one should hesitate to make this diagnosis in an adult person unless the summary of findings (small size, sharp circumscription, good maturation of the dermal component) clearly favors a nevus and the pagetoid spread shows some uniformity (usually limited to the lower part of the spinous cell layer, not asymmetrically localized to the edge of the lesion).

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Figure 12-28 Pagetoid Spitz’s nevus. this spindle and epithelioid melanocytic nevus from an 8-year-old child shows many melanocytes above the basal cell layer.

As a general rule, if a pathologist is not comfortable making a distinction between an unusual or atypical variant of Spitz’s nevus and melanoma, it is best to admit that and consult another pathologist. The consultant may also not be able to establish an unequivocal diagnosis or the initial pathologists may disagree with the consultant. In that case a pragmatic decision should be made. Spitzoid melanocytic proliferations with ambiguous findings that are associated with interobserver variability or controversy may be descriptively reported as atypical Spitz tumor or Spitzoid melanocytic tumor of uncertain malignant potential (STUMP). For such tumors, conservative complete excision is prudent practice. When several pathologists strongly suspect melanoma, most surgeons and patients opt for a treatment algorithm as for melanoma. This may include sentinel lymph node biopsy. If a lymph node biopsy is performed and contains metastatic melanoma (i.e., not a nodal nevus or falsepositive isolated immunoreactive cells, but dense clusters of atypical and/or mitotically active melanocytes in the subcapsular sinus or nodal parenchyma), there should be no more doubt about the malignant nature of the primary tumor draining to this node. However, we caution against re-classifying a primary lesion of atypical Spitz tumor as melanoma, if only small deposits of cytologically not obviously malignant melanocytes are detected in the sentinel lymph node draining such a lesion. Such deposits could represent an underrecognized pattern of benign nodal nevomelanocytes. Moreover even if a diagnosis of Spitzoid melanoma with positive sentinel lymph node is made, it is currently not known whether or not patients with these tumors have a similar prognosis as patients with “conventional” melanoma of similar thickness and stage. Among currently available ancillary techniques, testing for cytogenetic aberrations by comparative genomic

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hybridization (CGH) and/or fluorescence in situ hybridization (FISH) may improve the diagnostic accuracy of Spitzoid melanocytic proliferations. For example, a numerical increase in chromosome 11p is found in approximately one third of Spitz’s nevi and has not been observed in malignant melanomas, which are typically characterized by a complex karyotype with multiple deletions. Because aberrations of chromosome 6 are commonly found in melanomas, a FISH probe targeting loci on 6p25, 6q23, 6cent, 11q, has been developed and is commercially available. Preliminary data are promising that this FISH test can assist in gauging the odds of for the presence of a malignant melanoma. However, for CGH or FISH to become clinically more useful, more robust information needs to be provided on sensitivity and specificity. The test also needs to become more widely available. Currently only FISH is applicable to small lesions. We expect that cytogenetic and other molecular techniques will play an increasing role in the workup of diagnostically difficult Spitzoid and other melanocytic proliferations. Amelanotic Spitz’s nevi without a junctional component may be confused with nonmelanocytic lesions, such as reticulohistiocytoma and cellular neurothekeoma. Immunohistochemistry usually permits a clear distinction. Spitz’s nevi are positive for S-100 protein and Melan-A/Mart-1; reticulohistiocytoma and cellular neurothekeoma are melanocyte differentiation markers.

CONGENITAL MELANOCYTIC NEVI CliniCal Findings By definition the term congenital nevus implies the presence of a melanocytic lesion at birth. Such nevi tend to be larger (Fig. 12-29) than most ordinarily acquired nevi. They have arbitrarily been classified according to their size as small (less than 1.5 cm), medium (1.5 to less than 20 cm) and giant (20 cm or larger). Congenital nevi may occur in context with neurocutaneous melanosis, a syndrome in which melanocytic nevi are associated with leptomeningeal melanocytosis or melanoma. Congenital nevi, especially large variants, represent primarily a cosmetic problem, but there is also risk for the development of melanoma. Published data have likely exaggerated this risk because of referral bias and misdiagnosis of atypical melanocytic proliferations arising in congenital nevi as melanoma. Most dermal and/or subcutaneous nodules that develop within congenital nevi, especially giant congenital nevi, are clinically indolent, and represent so-called cellular and/or proliferative nodules. Patients with giant bathing trunk nevi may also have leptomeningeal melanocytosis and be at risk for the development of an intracranial melanocytoma or melanoma.

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Figure 12-29 congenital melanocytic nevus. A, Small congenital nevus. B, medium-sized congenital nevus. c, giant hairy nevus.

HistologiC Features Congenital melanocytic nevi may or may not have a papillomatous epidermal silhouette. Their superficial portion is similar to acquired nevi. However, congenital nevi typically show infiltration of melanocytes into the reticular dermis (Fig. 12-30). Melanocytes may even be present in the subcutis or deep soft tissues in a perivascular and/or interstitial distribution. In congenital nevi melanocytes are more often seen involving adnexal structures (eccrine ducts, folliculosebaceous units) (see Fig. 12-30, A) than in acquired nevi. Involvement of smooth muscle and peripheral nerve trunks may also be found. In some congenital nevi, melanocytes are present in the walls of blood vessels. Large congenital nevi may show prominent schwannian/neurofibromatous features and contain heterologous elements such as cartilage. Cellular and/or proliferative nodules may develop in congenital nevi, especially giant congenital nevi. They

congenitAL MeLAnocytic nevuS clinical Findings present at birth and/or clinically apparent in early childhood may be large (giant nevi)

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histologic Features overall symmetric with sharp peripheral borders Junctional component Similar to common nevi, but may be broader possible associated papillomatous epidermal hyperplasia possible pagetoid melanocytes Stromal component evidence of maturation Frequently involves reticular dermis, may extend into subcutis patterns of dermal involvement: diffuse, interstitial or perivascular » adnexal involvement is common » Nerve involvement may be seen » Schwannian differentiation may be prominent » Cellular and/or proliferative nodules may be present » heterologous elements may be present in large nevi

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Figure 12-30 congenital melanocytic nevus. A, Nevomelanocytes extend into the reticular dermis. B, Involvement of adnexal structures by melanocytes is seen.

manifest as areas of high cellular density that typically blend with the surrounding nevus component. Mitotic figures may be present (proliferative nodule). The melanocytes in these nodules may be fusiform and/or epithelioid. Cellular spindle cell nodules may have a primitive mesenchymal or sarcomatoid appearance. They may not be uniformly immunoreactive for melanocyte differentiation antigens or even S100 protein. On exceedingly rare occasions a tumor with histologic and immunohistochemical features indistinguishable from a sarcoma, such as a rhabdomyosarcoma, may arise in a giant congenital nevus.

diFFerential diagnosis The distinction of congenital nevi from acquired nevi is best made clinically. Although large and deep congenital nevi are histologically distinctive, many superficial dermal features associated with small congenital nevi may also be seen in acquired nevi. Confusion with in situ melanoma is possible, because benign pagetoid melanocytes may be found in congenital nevi. Attention to clinical and histologic context (stable lesion; otherwise benign nevus features, cytologically bland melanocytes in the spinous cell layer) is needed to avoid a diagnostic

error. In situ melanoma is best recognized by the presence of cytologically atypical pagetoid melanocytes and asymmetric extension of such cells peripherally beyond the dermal nevus component. With regard to the dermal or subcutaneous component, congenital nevi may contain areas of high cellular density without (cellular nodules) and/or with mitotically active melanocytes (proliferative nodules) that should be distinguished from melanoma (Figs. 12-31 and 12-32). Characteristically, nodular melanoma shows cytologic atypia distinctly different from the surrounding benign melanocytes with a fairly sharp demarcation between melanoma and nevus (Fig. 12-33). Within the melanoma nodule, there is a lack of maturation. Mitoses are often found. In contrast, cellular or proliferative nodules tend to mature and blend with the surrounding nevus cells. They also lack pleomorphism. Large congenital nevi in infants may also contain areas of high cellular density with mitoses, but without the formation of discrete nodules. Fascicles of spindle cells may simulate the appearance of a sarcoma. However, such densely cellular areas typically manifest an organoid growth pattern, blend with melanocytes, and mature toward their periphery to a schwannian phenotype. When congenital nevi show prominent differentiation along schwannian lines and contain heterologous elements, they may also be referred to as neurocristic

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Figure 12-31 Proliferative nodule in a giant congenital nevus. A, giant congenital melanocytic nevus with nodules. B, histologically, at the site of a nodule, a dense aggregate of melanocytes is seen in the dermis with mitotic figures.

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Figure 12-32 cellular spindle cell nodule in a giant congenital nevus. A, Compound melanocytic nevus with fusiform melanocytes filling the entire dermis and subcutis. B, a nodular spindle cell proliferation with cystic changes blends with the surrounding dermal neurotized nevus cells.

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Figure 12-33 Melanoma arising in association with a congenital nevus. A, a polypoid nodule is present in association with a medium-sized congenital nevus. B, Superficially, bland nevomelanocytes are present. Underneath is a dermal melanoma composed of atypical epithelioid tumor cells.

hamartoma. However, the latter term has generated some confusion, because it has been used in the literature for a spectrum of melanocytic proliferations, including large blue nevi, combined nevi, neurotized nevi, and congenital nevi with and without heterologous elements.

(nevus fuscoceruleus ophthalmomaxillaris) involves the segment of skin innervated by the first and second branch of the trigeminal nerve, and the nevus of Ito (nevus fuscoceruleus acromiodeltoideus) is present on the shoulder and/or upper arm. Acquired and congenital variants of dermal melanocytoses exist, which may manifest with an unusual anatomic distribution.

BLUE NEVI AND DERMAL MELANOCYTOSES CliniCal Findings Blue nevi comprise a spectrum of melanocytic lesions characterized clinically by a bluish appearance (Fig. 12-34). A blue nevus (BN) may be present at birth or appear at any time later in life. Preferred locations are the head and neck region, buttock, and dorsum of wrist or foot. Most BN are small and circumscribed lesions (see Fig. 12-34). However, unusual clinical variants exist, which may clinically present as large nodules (cellular BN) or plaques (plaque type BN) (Fig. 12-35) or as targetoid lesions (targetoid BN). The related dermal melanocytoses usually manifest clinically early in childhood and tend to be flat lesions of brown-bluish discoloration. The Mongolian spot typically affects the lumbosacral region, the nevus of Ota

Figure 12-34 common blue nevus. Common blue nevus presenting as a small bluish papule.

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Figure 12-35 Plaque type blue nevus. rare plaque-type blue nevus presenting as a large pigmented bluish-brown plaque with mottled pigmentation.

HistologiC Features Both BN and dermal melanocytosis are characterized by the presence of dendritic and/or fusiform melanocytes in the dermis and/or subcutis. Variable numbers of melanophages may be present. Except for combined or collision lesions, there is no associated junctional melanocytic proliferation. In dermal melanocytoses, the melanocytes are dispersed as solitary units and separated from each other by abundant intervening stroma (Fig. 12-36). Blue nevi represent more localized and cellular lesions (Fig. 12-37), in which melanocytes are more closely apposed to each other and may form fascicles or nests. There is a spectrum of histologic appearances of melanocytic proliferations that may be classified as BN.

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Figure 12-36 Melanocytosis. Scattered and widely spaced isolated fusiform melanocytes and melanophages are seen in the dermis.

The typical “common” BN (see Fig. 12- 37) is an intradermal proliferation of slender fusiform and dendritic pigmented melanocytes, which are often associated with melanophages and dermal fibrosis. Blue nevi are often present in association with a hair follicle. Variations may be seen with regard to size (Figs. 12-37 to 12-41), intralesional stromal fibrosis (see Fig. 12-38), pigmentation, cellularity, cellular composition (presence of another nevus-type component), cytology (e.g., epithelioid cells), and growth patterns (see Figs. 12-37 to 12-41). Accordingly a number of subtypes of BN have been proposed that reflect this spectrum (e.g., sclerosing BN, amelanotic BN, epithelioid BN, cellular BN). On rare occasion, a BN may contain a small benign trichoblastic proliferation (similar phenomenon as with superficial trichoblastomas and dermatofibromas) (see Fig. 12-39). B

Figure 12-37 common blue nevus. A, a perifollicular pigmented lesion is present associated with mild dermal fibrosis. B, It is composed of pigmented fusiform and dendritic melanocytes as well as macrophages.

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coMMon BLue nevuS clinical Findings » Bluish or gray to black appearance » Usually small papule » Common sites include dorsum of foot, wrist, and head histologic Features Usually oval-shaped lesion in reticular dermis Composed of slender fusiform and dendritic melanocytes, usually heavily pigmented with associated melanophages » Stromal fibrosis is common » periadnexal growth is common » Nerve involvement may be seen

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The sclerosing BN is characterized by prominent stromal fibrosis. It usually has an overall low cellular density (see Fig. 12-38). Amelanotic BN lacks readily detectable melanin pigment and may be confused with a dermatofibroma. The classic cellular BN shows a circumscribed nodular growth pattern (see Fig. 12-40). Bulging tonguelike extensions of densely cellular sheets into the deep dermis or subcutis may be present. Often a biphasic pattern is seen characterized by the presence of common blue nevus–like areas juxtaposed with more densely cellular paucimelanotic or amelanotic nested (see Fig. 12-40) or fascicular aggregates of melanocytes with pale cytoplasm and/or multinucleation (see Fig. 12-41, A). Focal cystic degeneration may occur in large lesions (see Fig. 12-41, B).

ceLLuLAr BLue nevuS clinical Findings » Sacral region/buttock, foot and scalp are most commonly affected » onset usually in childhood » Well-circumscribed gray-blue nodule histologic Features » localized to reticular dermis » Nodular expansile growth patterns of cellular aggregates » often bulging extensions seen at the base of the lesion » Biphasic pattern common with combinations of cellular nodules of spindle and/or epithelioid cells admixed with a background of features of common blue nevus (pigmented spindle and dendritic cells dispersed in a fibrous stroma with melanophages) » alveolar pattern may be present (fascicles of spindle cells compartmentalized by fibrous strands) » monophasic fascicular pattern differential diagnosis melanoma of soft parts (clear cell sarcoma) primary cutaneous or metastatic melanoma Nerve sheath tumor

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Figure 12-38 Sclerosing blue nevus. a paucimelanotic blue nevus is seen with prominent dermal fibrosis.

The epithelioid BN characterized by the presence of epithelioid melanocytes usually show an open chromatin pattern with or without a small distinct nucleolus. They are usually dispersed as solitary units in the reticular dermis without forming dense cellular aggregates. Although epithelioid melanocytes predominate, features of typical BN (small slender fusiform and dendritic melanocytes) are often seen, at least focally.

diFFerential diagnosis On rare occasions primary or metastatic melanoma may arise in association with or histologically mimic a BN, usually a cellular or epithelioid BN. Such primary tumors have historically been referred to as malignant blue nevus. The diagnosis of melanoma is straightforward if the histologic appearance is that of an obvious malignant tumor (necrosis, atypia, mitoses, infiltration growth), but it can be difficult when mitoses are rare and the degree of atypia is low. Monophasic cellular blue nevi may be large and densely cellular with fascicles of spindle cells lacking a nested growth pattern. Attention to the presence of aggregates or sheets of atypical epithelioid melanocytes with mitotic figures is important to recognize melanoma arising in a cellular

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Figure 12-39 Blue nevus with benign trichoblastic proliferation. A, Fusiform melanocytes fill the dermis and extend into the superficial subcutis. Small foci of basaloid proliferations are identified with dense surrounding stroma. B, the basaloid proliferation shows trichoblastic differentiation.

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Figure 12-40 cellular blue nevus. A, a densely cellular blue nevus is seen in the dermis with a deep tonguelike bulbous extension. B, Dense aggregates of cytologically bland epithelioid melanocytes are present in a background of typical blue nevus. a rare mitotic figure may be seen.

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Figure 12-41 cellular blue nevus. A, melanocytes in cellular blue nevi may have a pale cytoplasm and multinucleation. B, large lesions may show cystic changes with or without hemorrhage.

BN. Monophasic amelanotic variants of cellular BN may be confused with a sarcoma, such as synovial sarcoma or clear cell sarcoma. Melanoma metastatic to skin may have a BN-like clinical and histologic appearance. For such metastasis, clinical context is essential. Most BN-like melanoma metastases occur in the setting of a known prior melanoma. Histologically such lesions usually contain atypical epithelioid melanocytes with at least a rare mitotic figure.

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Figure 12-42 Pigmented epithelioid melanocytoma. A, Silhouette of a heavily pigmented tumor. B, It is composed of cytologically bland fusiform melanocytes and numerous melanophages.

The discussion of the differential diagnosis of BN also should address the term pigmented epithelioid melanocytoma, a recently proposed diagnostic entity for an epithelioid BN-like heavily pigmented melanocytic tumor of presumed low-grade malignant potential (Fig. 12-42). In our experience, several reported cases of pigmented epithelioid melanocytoma (PEM) seem to represent a spectrum of melanocytic tumors ranging from melanophage-rich BN or BN-like benign tumors to rare variants of melanophage-rich melanomas. Although

B

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the term PEM allows one to deal with diagnostically challenging heavily pigmented melanocytic tumors, for which a reliable distinction between melanoma and an unusual pigmented nevus is very difficult or may be impossible by light microscopic examination alone, we find the use of the term problematic for lesions, which previously would have been diagnosed as benign epithelioid BN or pigmented dermal spindle and epithelioid cell nevus. Additional confusion about the biologic potential of the PEM comes from reports that pigmented melanocytes and melanophages may be found in the sentinel nodes draining such lesions. Such findings are no proof of malignancy, because similar features can be observed with nodal blue nevi. In our view whenever possible pathologists should attempt to make a clear distinction between a pigmented nevus and pigmented melanoma without using a diagnostic category that blurs that distinction.

line nevus for such nevi. Similar features may also be present in nevi of the genital region. Nevi at acral sites, especially at palms and soles, may show discrete columns of melanin pigment in the stratum corneum (Fig. 12-44). There may be ascent of cytologically bland melanocytes as solitary units of nests into the mid and upper epidermis (see Fig. 12-44). Thus pagetoid spread of melanocytes (pagetoid melanocytosis) per se is not sufficient for a diagnosis of melanoma in situ at an acral site if the lesion otherwise shows features of a benign nevus. In acral nevi, melanocytes may be dispersed prominently along eccrine ducts.

NEVUS SPILUS/SPECKLED NEVUS CliniCal Findings

MELANOCYTIC NEVI OF SPECIAL ANATOMIC SITES The spectrum of histologic features of melanocytic nevi depends to some degree on anatomic site. Knowledge of the spectrum of site-dependent features is important when one weighs the significance of various findings for the final diagnosis. Nevi at flexural sites, including axilla, umbilicus, and groin, for example, may have large nests and/or great variation in the size and shape of nests (Fig. 12-43). Cellular dyscohesion of nevomelanocytes is not uncommon. Often there is a complex pattern of associated epidermal hyperplasia. Focal pagetoid melanocytes may be present. Some have used the term milk

The nevus spilus or speckled lentiginous nevus is a lightly pigmented macular lesion (ranging from less than 1 cm to greater than 20 cm in size) that contains dark speckles (Fig. 12-45, A) that may be flat or raised. It may be present at birth, but more commonly develops in childhood, with a predilection for the trunk and extremities.

HistologiC Features The tan macular component is histologically characterized by basal layer hyperpigmentation, often accompanied by a slight increase in the density of solitary melanocytes (similar to a lentigo). The histologic correlate of the clinically darker speckles may be that of a lentigo simplex, lentiginous junctional (Fig. 12-45, B), compound, or intradermal melanocytic nevus. Various histologic types of nevi may be represented within the dark spots of speckled nevi.

AcrAL MeLAnocytic nevuS clinical Findings any age Usually small (except for dysplastic or congenital acral nevi)

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Figure 12-43 Melanocytic nevus of flexural site. a compound melanocytic nevus is present with many large nests and variation in the size and shape of nests.

histologic Features Symmetric and circumscribed predominant nested growth pattern pagetoid melanocytes may be present Inflammatory stromal changes are uncommon

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B

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Figure 12-44 Melanocytic nevus of acral skin. A, a circumscribed pigmented macule is seen near the toenail. B, Silhouette of nevus with predominant nested pattern and sharp lateral demarcation. c, a compound melanocytic nevus with superficial dermal pigmentation is present. a vertical column of melanin pigment is seen in the stratum corneum. d, pagetoid spread of cytologically bland melanocytes may be seen in an acral nevus.

MISCELLANEOUS UNUSUAL MELANOCYTIC NEVI Additional types of melanocytic nevi have been described, which are uncommon. Three such types are briefly presented here: the so-called deep penetrating nevus (DPN), plexiform spindle cell nevus, and the desmoplastic nevus.

DEEP PENETRATING NEVUS In its classic manifestation the DPN is a dome-shaped papule with various shades of color. Histologically, it is characterized by a wedge-shaped silhouette (Fig. 12-46). It often extends into the deep dermis and may involve the subcutis. The melanocytes of a DPN may be large epithelioid and/or fusiform in appearance. They are

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B

Figure 12-45 nevus spilus. A, a light brown macular lesion is present with darker brown spots within it. B, there is a focus of a lentiginous melanocytic proliferation in a background of basal layer hyperpigmentation.

B A

Figure 12-46 deep penetrating nevus. A, a pigmented melanocytic nevus with a wedge-shaped silhouette is seen. B, pigmented spindle and epithelioid melanocytes are present as well as melanophages.

often pigmented. Melanophages are present in variable numbers. Published definitions of DPN are not precise and suggest overlap with variants of BN, pigmented Spitz’s nevi, plexiform spindle cell nevus, and even melanoma. One should hesitate to make a diagnosis of

atypical DPN. We have seen melanocytic proliferations designated as DPN by experienced pathologists, which were followed by the development of metastatic melanoma. Those cases were notable for the presence of large epithelioid melanocytes with mitotic figures.

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PLEXIFORM SPINDLE CELL NEVUS This nevus shows similar features as the spindle cell variant of DPN and many pathologists regard them as the same lesion. In contrast with the typical DPN, the plexiform spindle cell nevus shows a more prominent growth pattern along neurovascular bundles.

DESMOPLASTIC (SCLEROSING) MELANOCYTIC NEVUS The desmoplastic nevus is a compound or dermal melanocytic nevus associated with prominent dermal fibrosis. The morphology of the melanocytes is variable, ranging from small epithelioid (ordinary desmoplastic nevus) to large cells (desmoplastic Spitz’s nevus) (see Fig. 12-26) or slender fusiform and dendritic cells (sclerosing BN). The main significance of a sclerosing nevus is potential confusion with desmoplastic melanoma. Sclerosing nevi are distinguished from melanoma by a usually symmetric silhouette. Mitotic figures are usually absent in dermal melanocytes. In contrast with desmoplastic melanoma, most sclerosing nevi are small symmetric superficial dermal lesions. They tend to be diffusely immunoreactive for Melan-A, but show minimal staining for Ki-67.

ScLeroSing MeLAnocytic nevuS clinical Findings often thought to be a dermatofibroma or scar

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histologic Features Symmetric and circumscribed Benign junctional melanocytic proliferation, if present extent in depth usually confined to superficial dermis maturation usually apparent (larger cells and cell clusters superficially) lack of mitotic figures in dermal melanocytes

MELANOCYTIC NEVI WITH PHENOTYPIC HETEROGENEITY Melanocytic nevi may show combined features of two or more separate nevus types within the same lesion. Such nevi are commonly referred to as combined nevi. Any admixture of melanocytic phenotypes may occur in the same lesion. The combination of blue nevus and “ordinary” dermal acquired nevus seems to be the most common form of combined nevus (Fig. 12-47, A). Other variations include Spitz’s nevus or deep penetrating nevus combined with an ordinary or congenital nevus (Fig. 12-47, B). The so-called inverted type A nevus may also be discussed in this context. It is characterized by the presence of discrete nests of large (variably pigmented) epithelioid melanocytes set in the dermis of an ordinary or congenital nevus. Some have referred to this phenomenon descriptively as “melanocytic nevus with focal dermal epithelioid cell component” (Fig. 12-48). Such epithelioid cells may be present in the deep portion of a nevus and complicate the assessment of maturation. When a morphologically distinct population of melanocytes is found separate from the nevus background, one should consider the possibility not only of a combined nevus, but also of melanoma arising in the dermal component of a melanocytic nevus. Although such a process of malignant transformation without involvement of the dermal-epidermal junction is rare, it does occur in congenital and acquired nevi. Melanoma needs to be suspected, if there are cytologically atypical epithelioid cells forming expansile nodular aggregates and mitotic figures are identified (see Fig. 12-33). In contrast a combined nevus is favored, if the cytologically different component shows overall features of a nevus (lack of or only minimal atypia, good evidence of maturation) and blends with the other nevus component.

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variants » Common nevus with sclerosis » Congenital nevus with sclerosis » Sclerosing blue nevus » Sclerosing Spitz’s nevus immunophenotype most are positive for melan-a/mart-1 (in contrast with desmoplastic melanoma)

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differential diagnosis Desmoplastic melanoma Dermatofibroma

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recurrent/PerSiStent MeLAnocytic nevuS clinical Findings » repigmentation at the site of a scar histologic Features Intraepidermal melanocytes overlying the scar may show marked architectural disorder, including pagetoid spread of melanocytes » an associated dermal nevus component may be present within the scar » hyperpigmentation is common within melanocytes and keratinocytes » Intraepidermal melanocytes peripheral to the scar show a predominant nested pattern as expected for a junctional nevus

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Figure 12-47 combined ordinary and blue nevus. A, a compound melanocytic nevus is present, the dermal component of which shows in part features of blue nevus. B, Combined congenital and deep penetrating melanocytic nevus.

Figure 12-48 Melanocytic nevus with large epithelioid cells. Clusters of large epithelioid melanocytes are present in a background of small epithelioid nevomelanocytes.

RECURRENT/PERSISTENT MELANOCYTIC NEVI Melanocytic nevi may clinically “recur” at the site of a prior biopsy. Such a recurrence is usually because of growth of melanocytes left behind from an incompletely removed nevus. Histologically the junctional/ intraepidermal growth pattern of recurrent/persistent

nevi may show features overlapping with those of in situ melanoma (pseudomelanoma), such as the presence of pagetoid spread, confluent nests at the dermal-epidermal junction and a predominance of solitary units of melanocytes (Fig. 12-49). In a recurrent/persistent nevus phenomenon, the atypical melanocytic growth pattern is restricted to the epidermis overlying the scar. An unequivocally benign nevus component is commonly present adjacent or underneath the atypical proliferation. Furthermore the melanocytes of recurrent nevi usually lack marked cytologic atypia. In contrast, in situ melanoma at the site of a scar (from a previously biopsied nevus or melanoma) usually extends significantly beyond the area of the dermal scar with an ill-defined peripheral border. In difficult cases it is helpful to review the prior biopsy, because what is reported to have been a prior benign or atypical nevus may represent an in situ melanoma that was not recognized as such.

PRIMARy MELANOMA The number of people who develop melanoma continues to increase. The reported incidence in the white population has more than tripled over the past 20 years. Approximately 69,000 new cases of invasive melanoma are expected in the United States during the year 2009. There is emerging evidence for multiple different

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MeLAnoMA—cLinicAL FActS incidence approximately 110,000 new cases expected in the USa for 2008 60,000 invasive melanoma 50,000 in situ melanoma Fifth most common cancer in women, sixth most common in men (North america) » most common cancer in white women aged 25 to 29

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risk Factors Family history of melanoma Numerous melanocytic nevi Fair skin UV exposure age greater than 50 genodermatoses: xeroderma pigmentosum or familial atypical mole syndrome

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clinical Warning Signs for Melanoma: ABcde rule

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Asymmetry Border irregularity color variegation diameter (greater than 6 mm) evolving (change of a pigmented lesion)

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pathways that can result in melanoma, with both genetic as well as environmental factors. The risk for developing a melanoma is increased if there is a family history of melanoma or a clinical phenotype of numerous nevi, especially numerous atypical nevi. Melanomas are more common in fair-skinned individuals with sun sensitivity and a history of excessive sun exposure. The risk for melanoma increases with age. Other risk factors include DNA repair defects (xeroderma pigmentosum), a prior history of melanoma, and immunosuppression.

CliniCal Findings Melanoma is clinically suspected if a preexisting mole is changing or a new pigmented lesion appears that shows worrisome features, such as large size, variability in colors, surface texture, irregular peripheral borders (Fig. 12-50), or is symptomatic (itch, pain, tenderness, bleeding). Although the clinical impression is a good guide for the diagnosis, especially in well-developed lesions, there are many exceptions, and the accuracy of

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Figure 12-49 recurrent melanocytic nevus. A, pigmentation is seen within a scar of the site of a previously biopsied nevus. B, histologically a melanocytic nevus is present in association with a dermal scar. c, the junctional melanocytic proliferation shows architectural disorder.

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D C

Figure 12-50 clinical appearance of conventional melanoma types. A, asymmetric complex silhouette of a melanoma from the trunk (superficial spreading melanoma). B, asymmetric complex macular pigmented lesion on the face (lentigo maligna). c, Nodular melanoma. d, acral melanoma.

the clinical diagnosis is less than perfect (approximately 60%). Histologically unequivocal melanoma may clinically be confused with a benign or atypical nevus or even a keratosis. If no pigment is visible clinically (amelanotic melanoma), other tumors, such as basal cell carcinoma, may be suspected instead of melanoma. Likewise a clinically complex pigmented lesion suspected to be melanoma may be histologically banal (e.g., a macular pigmented seborrheic keratosis or solar lentigines).

HistologiC Features: general Considerations For tHe diagnosis oF MelanoMa Histologic examination and clinicopathologic correlation represent the gold standard for the diagnosis of melanoma. Among experienced pathologists histologic assessment of melanocytic lesions is fairly accurate and reliable in the majority of cases, but cannot be expected to be perfect in every case. Controversy arises especially when melanoma mimics a Spitz’s nevus or the biopsy

sample is small. A number of different clinical and histologic variants of melanoma have been described. A diagnosis of melanoma is usually not based on a single histologic finding, but on a constellation of clinical and histologic parameters. The proportional weight of various features for the diagnosis depends on the degree to which they are developed and the clinical context. Pagetoid spread of melanocytes, for example, is a finding commonly associated with in situ melanoma (de novo or associated with a melanocytic nevus). If pagetoid melanocytes are prominent, cytologically atypical, and displayed in a chaotic pattern, the diagnosis of intraepidermal melanoma is certain. Focal pagetoid spread, however, may not be sufficient for a diagnosis of melanoma. A benign or atypical melanocytic nevus may show pagetoid spread of usually bland melanocytes at the site of prior trauma/irritation or surgery. Furthermore acral, congenital, and Spitz’s nevi may show focal pagetoid spread of nevomelanocytes. In many cases assessment of the silhouette and gestalt of a lesion (comparing it with stored mental images of previously observed nevi and melanomas) is diagnostic

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SynoPSiS oF conventionAL MeLAnoMAS Superficial Spreading type

nodular type

clinical Findings Intermittent sun-damage: most common on the trunk and extremities » Individuals aged 20 to 50 » may arise de novo or in association with melanocytic nevi

clinical Findings » most common on trunk and legs » history of rapid growth » may arise de novo or in association with melanocytic nevus

histologic Features » Nests and single cell scatter of melanocytes within the epidermis

» »

»

histologic Features Invasive melanoma with no detectable in situ component If in situ melanoma is present, it does not extend more than 3 rete ridge peripheral to the lateral edge of the invasive tumor

Lentigo Maligna type clinical Findings » Chronic sun-damage: most common on head and neck and arms » Fair-skinned older people (mean age at diagnosis: 65 years) » Usually arises de novo; slowly growing; rarely associated with nevus histologic Features predominance of solitary units of melanocytes at the dermalepidermal junction, but may also have nests and pagetoid cells

»

hiStoLogic diAgnoSiS oF conventionAL (tyPicAL) PriMAry cutAneouS MeLAnoMA

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Silhouette: asymmetry Borders: Usually ill-defined Size: often greater than 4 mm in diameter, but bona fide small (2 mm) diameter melanomas exist Intraepidermal melanoma component Irregular pagetoid spread and/or broad lentiginous junctional proliferation predominance of solitary units of melanocytes markedly irregular disposition of melanocytes Complex and oddly shaped junctional nests marked confluence of melanocytes along the dermal-epidermal junction marked dyscohesion of melanocytes Cytologic atypia of melanocytes (variable) Dermal and/or subcutaneous melanoma component Complex asymmetric growth pattern lack of maturation or only minimal maturation expansile nodules oddly shaped nests mitotic figures may be present Cytologic atypia of melanocytes (variable) Stromal changes lichenoid inflammatory reaction may be present Fibrosis and dermal regression may be present associated surface epiphenomena » Ulceration and/or “consumption of the epidermis” (obliteration/ effacement of rete ridges) are more often seen with melanomas than with nevi

Acral type clinical Findings most common subtype worldwide (majority of melanomas in dark-skinned individuals) » palms and soles; subungual » may arise de novo or in association with melanocytic nevi

»

histologic Features most often displays a lentiginous pattern with a predominance of solitary units of melanocytes along dermal-epidermal junction

»

for an experienced pathologist. For didactic (and for beginners also practical) purposes, however, a stepwise approach is presented here to discuss various diagnostic features. Scanning magnification allows assessment of the overall symmetry of a lesion. The more complex and asymmetric a lesion is, the more likely it represents melanoma (Fig. 12-51). With thick primary tumors the presence of a malignant melanoma may be readily apparent by the presence of an ulcerated tumor with dense sheets of tumor cells (see Fig. 12- 51) without any resemblance to a benign melanocytic nevus. Most of the time, however, pathologists need to interpret thinner tumors, which requires systematic analysis of parameters outlined in the following to distinguish them from melanocytic nevi. For lesions with an intraepidermal melanocytic proliferation (with or without an associated dermal component), it helps to determine first whether or not in situ melanoma is present. A different approach is needed for melanomas lacking an intraepithelial component.

HistologiC Features For tHe diagnosis oF MelanoMa in situ The majority of cutaneous melanomas begin as intraepidermal melanocytic proliferations with or without an associated melanocytic nevus. As a general rule in situ

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A B

Figure 12-51 Melanoma. A, the silhouette of the tumor is asymmetric. B, polypoid melanoma.

melanomas are characterized by a broad irregular proliferation of atypical melanocytes within the epidermis. Solitary units of melanocytes tend to dominate over nests, at least focally. They tend to fill the spaces between rete ridges. Melanocytes may be present at the mid or upper spinous cell layer (pagetoid spread). At one end of the spectrum pagetoid spread may be well developed (pagetoid in situ melanoma) (Fig. 12-52). At the opposite extreme, few or no pagetoid cells may be noted and melanoma cells are primarily distributed as solitary units along the dermal-epidermal junction (lentiginous pattern) (Figs. 12-53 and 12-54). Overlap of these patterns in the same lesion is not uncommon. Other features that help identify in situ melanoma are the presence of solitary units of melanocytes within epithelial structures of adnexa (follicular infundibulum or eccrine duct), marked confluence or nests along the A

dermal-epidermal junction as well as dyscohesion of cells within often large and irregularly shaped cell aggregates along the dermal-epidermal junction. There are often secondary epidermal (e.g., effacement of rete ridges with thinning of the epidermis, also referred to as

diFFerentiAL diAgnoSiS oF PAgetoid MeLAnocytoSiS

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melanocytic nevus Irritated (rubbed/scratched) nevus recurrent/persistent nevus (prior surgical trauma) acral nevus Congenital nevus Spitz nevus melanoma in situ

B

Figure 12-52 Melanoma in situ, pagetoid pattern. A, De novo pagetoid melanoma in situ. B, pagetoid melanoma in situ arising in association with a melanocytic nevus.

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Dermatopathology

A

B

C

D

Figure 12-53 Melanoma in situ, lentiginous pattern. A, an atypical proliferation of solitary units of melanocytes is present along the dermal-epidermal and infundibular dermal junctions. B, Solitary units of melanocytes predominate along the dermal-epidermal junction. epidermal rete ridges are effaced. there is marked solar elastosis. c, however, nests of melanocytes are also seen. Some melanocytes are multinucleated. d, Focally pagetoid intraepidermal spread of melanocytes is present. A–d are different foci from the same melanoma.

consumption of the epidermis) and/or dermal stromal alterations (e.g., lichenoid inflammatory reaction). Cytologic atypia of melanocytes may be prominent, but is at times only mild, especially in lentiginous melanomas of chronically sun-damaged skin or at mucosal sites. In the majority of cases, analysis of the architecture of the lesion, in particular the growth pattern of melanocytes is the key to the diagnosis. On occasion in particular with small and paucicellular lesions, the presence of cytologic atypia may carry more weight for judging the nature of a lesion.

diFFerential diagnosis oF MelanoMa in situ When pagetoid spread is noted, especially in association with features of an associated melanocytic nevus, one needs to bear in mind that trauma, nevus type, or anatomic site may account for some pagetoid spread.

Lentiginous melanoma in situ should be distinguished from solar lentiginous melanocytic hyperplasia, lentigo simplex, and atypical lentiginous junctional melanocytic nevi. The recognition of a lentiginous melanoma is straightforward if one deals with the excision of a large irregular junctional melanocytic proliferation of a clinically suspected melanoma. It can be very difficult or impossible, however, on a partial biopsy, if one does not know the size of the lesion. The distinction of a lentiginous melanoma in situ of chronically sun-damaged skin (lentigo maligna melanoma in situ) from solar melanocytic hyperplasia is best accomplished by comparing the lesional cellular density and atypia of melanocytes with a reference (control) biopsy of clinically “normal” skin. Too often, such a “control” biopsy is not available. In this instances, a reference for “normal” skin may be found in negative margins of an excision, other anatomically matched additional biopsies (e.g., for basal cell carcinoma) from the same patient. If no

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A

B

C

Figure 12-54 Acral melanoma in situ. A, acral in situ melanoma with prominent lentiginous pattern: melanocytes are disposed as solitary units along the base of elongated rete ridges. B, acral in situ melanoma with pagetoid pattern. c, Subungual melanoma in situ.

reference is available, the presence of confluent melanocytes at the dermal-epidermal junction strongly favors melanoma. The distinction of an atypical lentiginous junctional melanocytic nevus from in situ melanoma can be problematic as well. Small foci in a lentigo maligna melanoma in situ may be indistinguishable from histologic features

of a lentiginous junctional dysplastic nevus. Clinical features are important here (size, location, complexity to the clinical eye or dermoscopically assisted visual examination). Flat lesions associated with an atypical lentiginous junctional melanocytic proliferation located in the head and neck region of elderly individuals with chronic sun damage are more often than not in situ melanomas.

472 A diagnosis of nevus can still be made if the lesion has been present for some time, is small and circumscribed, and its histology shows nests predominating over solitary units of melanocytes. A diagnosis of in situ melanoma is favored if solitary units predominate, become confluent at the dermal-epidermal junction, and show an ill-defined border. In the absence of an associated dermal melanocytic nevus component, involvement of adnexal epithelium (proliferation of melanocytes along the infundibular dermal junction or along terminal sweat ducts) also favors melanoma over a junctional nevus. The presence of several multinucleated cells (starburst giant cells) favors in situ melanoma, but is in itself not specific, because it may also be seen with nevi. Skip areas are not uncommonly found in lentigo maligna and are diagnostically helpful in their distinction from a junctional nevus, which rarely shows this phenomenon. Skip areas refers to a seemingly discontinuous growth of junctional melanocytes in a two-dimensional plane. A proliferation of atypical junctional melanocytes along the dermal-epidermal junction is interrupted by a stretch of skin with features of solar lentigo devoid of a significant increase in the density of melanocytes or by skin with no significant pathologic changes (appears normal).

HistologiC Features For tHe diagnosis oF invasive MelanoMa

Dermatopathology

Figure 12-55 invasive melanoma. melanocytes in the dermis resemble intraepidermal melanoma cells. the dermal melanocytes lack an orderly nested pattern and diffusely infiltrate the dermis.

In situ melanoma may erroneously be interpreted as invasive tumor when it colonizes adnexal structures and expands within them (Fig. 12-56). Another problem of potential over- or underestimation of the extent of invasion may occur when a melanoma arises in association with a melanocytic nevus. The distinction is easy if there

If a diagnosis of in situ melanoma has been established and there is an associated dermal melanocytic component, the issue is whether the dermal melanocytes represent a nevus, invasive melanoma, or perhaps a mixed population of melanoma and nevus. The issue of invasion may be readily apparent if the dermal component is deeply infiltrative with an asymmetric growth pattern. Furthermore the presence of atypical mitotically active melanocytes in the dermis cytologically similar to the in situ melanoma component makes a diagnosis of invasive melanoma (Fig. 12-55) straightforward.

diFFerential diagnosis oF PriMary invasive MelanoMa If a lesion is recognized as melanocytic in origin, the main differential diagnosis is between primary cutaneous melanoma and a melanocytic nevus. Melanoma may simulate the growth pattern of or arise in association with any kind of nevus. The differential diagnosis of various problems, such as the distinction of superficial spreading melanoma from a dysplastic nevus or a sclerosing nevus from desmoplastic melanoma, is discussed in more detail under the respective nevus or melanoma subtype.

Figure 12-56 in situ melanoma mimicking invasive melanoma. melanoma cells are confined to the epithelial site of the basement membrane within the sweat gland apparatus and a hair follicle.

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Figure 12-57 Melanoma arising in association with a nevus. there is a clear distinction between the cytology of the melanoma and nevus cells.

is marked difference in the cytology and growth patterns between melanoma and nevus (Fig. 12-57). The recognition and measurement of invasion, however, can be very difficult when the invasive tumor lacks marked atypia and maintains a nested growth pattern. If a lesion is amelanotic, primary melanoma may be confused with a number of benign or, more often, malignant nonmelanocytic tumors. Benign tumors, which may be misinterpreted as melanoma on routine hematoxylin and eosin–stained sections, include foam- and giant-cell poor xanthogranuloma or fibromas incidentally associated with a nevus. (They may be misdiagnosed as desmoplastic melanoma.) Malignant tumors, which may show overlap with melanoma, include poorly differentiated carcinomas, miscellaneous sarcomas, and anaplastic large cell lymphoma. Immunohistochemical studies usually allow a definitive determination of the line of differentiation, and have rendered confusion of a primary melanoma with a malignant nonmelanocytic tumor an uncommon event.

HistologiC ParaMeters relevant For Prognosis A number of histologic features have been identified that statistically correlate with patient outcome. Although it is impossible to precisely predict the clinical outcome for an individual person, prognostic parameters are relevant for clinical trials to stratify patients into risk groups to better identify potential effects from surgical or medical treatment modalities (versus the natural history of the disease). Risk assessment is also relevant for decisions on the extent of clinical workup and follow-up. For the care for an individual patient, it is important to realize that statistical data are probability

scenarios for patient populations with certain characteristics. They do not predict a particular individual’s fate. There is always hope for survival against the odds. Likewise there is no guarantee for a good outcome in spite of favorable statistical data. Tumor thickness has been established as the most powerful predictor in many multivariate analyses of large cohorts. Other parameters of prognostic significance include ulceration, Clark levels, lymphovascular and/or perineural invasion, tumor mitotic rate, and the presence or absence of satellite metastases. In the most recently revised melanoma staging system of the AJCC (2002), only tumor thickness, ulceration, and Clark level are used as parameters for the T–classification. Tumor mitotic rate will likely be included into the next staging system. Although lymphovascular, intraneural or perineural invasion are not part of the staging system, their reporting is encouraged. The presence of lymphovascular invasion clearly correlates with metastatic disease. Nerve involvement is associated with increased local recurrence. The presence of satellites affects the N-classification. tuMor tHiCkness

Tumor thickness is measured with an ocular micrometer according to Breslow as the greatest vertical distance (expressed in millimeters) between the deepest invasive melanoma cells and the granular cell layer of the overlying epidermis. If the overlying epidermis is ulcerated, the base of the ulcer is taken as reference point. When there is an associated melanocytic nevus or in situ melanoma within an adnexal structure, the measurement should not include the nevus or in situ melanoma, but be limited to what can be recognized unequivocally as invasive melanoma. ulCeration

Ulceration is detected as a tumor-related defect in the skin surface. The epidermis is missing and there is a stromal inflammatory and granulation tissue type reaction. Ulceration because of prior surgical procedure or focal excoriation should not be designated as tumor ulceration. In tumor-induced ulceration the epidermis adjacent to the ulcer is often effaced and thinned. MiCroanatoMiC (Clark) level

Clark levels indicate which microanatomic compartments are involved by melanoma. Clark level I represents intraepidermal or in situ melanoma (Fig. 12-58, A). Clark level II reflects partial invasion of the papillary dermis (Fig. 12-58, B). Clark level III refers to melanomas that fill and/or expand the papillary dermis (Fig. 12-58, C). Once invasive melanoma has entered the reticular dermis and tumor cell aggregates are completely surrounded by reticular dermal collagen, a Clark

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A

C

B

D

E

Figure 12-58 Microanatomic (clark) levels. A, Clark level I: melanoma is confined to within the epidermis. B, Clark level II: melanoma is present in the epidermis and papillary dermis without filling the papillary dermis. c, Clark level III: melanoma fills and expands the papillary dermis. d, Clark level IV: melanoma extends into the reticular dermis. Coarse reticular dermal collagen bundles surround melanoma cells. e, Clark level V: melanoma extends into subcutaneous adipose tissue.

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level IV is assigned (Fig. 12-58, D). Melanomas invading the subcutaneous fat or deeper (e.g., muscle or bone) are of Clark level V (Fig. 12-58, E). tuMor MitotiC rate

Tumor mitotic rate (TMR) is measured as the number of mitotic figures of melanoma cells per millimeter squared of invasive tumor. For practical purposes, invasive melanoma is scanned for mitotic figures and the mitotic count is started at an area where mitoses can easily be spotted (mitotic hot spot). Using a 40× objective, additional randomly chosen high power fields in the area of invasive melanoma are then examined for tumor cells in mitosis until an area of 1 mm2 is covered. With many current microscopes this implies examining five high power fields. However, it is best to calibrate one’s own microscope for the area examined at high power and to verify how many high power fields are necessary to cover 1 mm2. lyMPHatiC or Blood vessel invasion

Figure 12-60 Blood vessel invasion. tumor cells are present in the wall of a blood vessel.

nerve involveMent

Lymphovascular invasion is diagnosed by the presence of intravascular tumor deposits that cannot be attributed to “artifacts” from using an unclean knife or pushing tumor tissue into empty spaces during cutting. Unequivocal vascular invasion is present, if tumor cells within a vascular lumen are intimately admixed with blood cells, focally adherent to the vessel wall (Fig. 12-59) or, in the case of large blood vessels, seen within the vessel wall (Fig. 12-60). Vascular invasion is an uncommon finding in primary melanomas. It is usually seen in association with large tumors. A related term is angiotropism, which refers to the cuffing of vessels by melanoma cells. Its presence is also an adverse prognostic feature.

Melanoma may involve the sheath of a nerve (perineural invasion) or extend into the nerve (endoneurial invasion). Nerve involvement should not be regarded as proof of malignant melanoma. It can be seen in congenital or neurotized acquired ordinary and blue nevi. Nerve involvement is often used synonymously with neurotropism. Some pathologists, however, use the term neurotropism to indicate the presence of a neuroma-like growth pattern and line of differentiation by a melanoma or nevus. Neurotropic lesions typically show involvement of multiple nerve bundles. Nerve involvement by melanoma is illustrated in Figure 12-61.

Figure 12-59 Lymphatic invasion. Clusters of melanoma cells are present in a lymphatic channel.

Figure 12-61 nerve involvement. a peripheral nerve is invaded and surrounded by fusiform melanoma cells.

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satellites/loCoregional Cutaneous Metastases

Satellites are locoregional melanoma metastases that may be clinically apparent (Fig. 12-62) or only be seen under the microscope (microscopic satellites) as tumor cell aggregates away from the main invasive tumor mass (not artifactually separated by the plane of section by regression) (Fig. 12-63). tuMor-inFiltrating lyMPHoCytes

A few studies have suggested that the presence of a “brisk” infiltrate of lymphocytes infiltrating melanoma is associated with a more favorable outcome. A brisk infiltrate is defined as a dense infiltrate of lymphocytes that involves either diffusely the entire invasive tumor or at least surrounds and disrupts the entire advancing periphery of invasive melanoma (Fig. 12-64). Any lymphocytic infiltrate short of these features is classified as “nonbrisk.” (Most melanomas have a nonbrisk

Figure 12-64 tumor-infiltrating lymphocytes. the invasive front of the melanoma is surrounded and infiltrated by lymphocytes.

infiltrate.) If there are no lymphocytes or lymphocytes that do not infiltrate and disrupt the tumor, they are designated as absent. regression

Figure 12-62 Melanoma with satellites, clinical. a primary melanoma nodule of the scalp is surrounded by many small satellite nodules.

Regression refers to features that suggest a loss or disappearance of melanocytes, generally assumed to be an immunologically mediated phenomenon. Regression is best recognized of there is an area within a melanoma that suddenly lacks melanocytes within the dermis and/or epidermis in the absence of a prior biopsy. Histologic traces of regression include various stromal alterations, such as inflammation, edema and/or fibrosis, hypervascularity, and melanophages (Fig. 12-65). On occasion the entire tumor may be regressed and only the silhouette of a presumed regressed melanocytic lesion can be found. There is significant interobserver variability in the assessment of regression. The main significance of reporting regression lies in the fact that if in situ melanoma is found together with features of regression, associated invasive melanoma can no longer be excluded. It is important to realize, however, that not every focus of regression implies regressed melanoma. It may also represent a regressed nevus component. Regression with melanophages may also be associated with nonmelanocytic tumors, such as a basal cell carcinoma. Furthermore not every cluster of melanophages or lymphocytes implies regression.

COMMON (CONVENTIONAL) VARIANTS OF MELANOMA Figure 12-63 Melanoma with satellites, histology. a primary melanoma is seen as well as melanoma nodules in the dermis separate from the main tumor mass.

Cutaneous melanomas have historically been classified into four major types: superficial spreading, lentigo maligna, acral lentiginous, and nodular. The first three

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A

B

Figure 12-65 Melanoma with regression. A, Features of regression include an altered stroma (edema, hypervascularity, inflammation) and loss of melanocytes. B, primary nodular melanoma with adjacent features of regression.

types are classified by the growth pattern of the intraepidermal (in situ) melanoma component. Superficial spreading melanoma is characterized by prominent intraepidermal pagetoid spread of melanoma cells (pagetoid in situ melanoma) and/or presence of many wellformed junctional melanocyte nests. This type of melanoma is commonly associated with melanocytic nevi. Melanomas of lentigo maligna and acral lentiginous types show a predominance of solitary units of melanocytes at the dermal-epidermal junction (lentiginous melanoma). Lentigo maligna is associated with marked solar elastosis and usually affects the head and neck region. Acral lentiginous melanomas occur by definition at acral sites. Nodular melanoma refers to an invasive melanoma without or only a minimal detectable in situ component. There has been much debate about the validity of this classification scheme and to what extent the dominant histologic growth pattern is a reflection of anatomic site. Because this historical classification scheme lacks prognostic value and there is overlap in histologic patterns (e.g., lentigo maligna or acral melanomas may also show pagetoid growth patterns) as well as significant interobserver variability, many pathologists no longer use this classification in their daily practice. However, recent observations that the histologic patterns correlate to some extent with distinct mutations (see the following) have led to renewed interest the classification of melanomas: Histologic pattern analysis may provide a screening method for the probability of molecular pathway alterations that may be relevant for therapy. Melanomas have also been classified by growth phases. The so-called radial growth phase refers to a flat peripheral spread of melanoma and is said to lack competence for metastasis. The so-called vertical

growth phase reflects invasive downward growth and indicates the ability to metastasize. In this concept radial and vertical growth phases are not entirely synonymous with in situ and invasive melanoma. Radial growth phase is said to include intraepidermal (in situ) melanomas with isolated small solitary units or clusters of melanocytes in the papillary dermis without mitotic figures and compact dermal tumor cell aggregates larger in size than the largest junctional melanocytic nest. The concept of radial and vertical growth phase has been incorporated into some prognostic models, but has been questioned by others on philosophical and practical grounds, because some melanomas said to be confined to the radial growth phase were found to have metastasized on clinical follow-up, and many melanomas said to be in the vertical growth phase are cured by simple excision. There is emerging evidence that melanomas are genetically heterogeneous and can be subclassified by molecular signatures (profile of chromosomal aberrations) and mutations (e.g., BRAF, KIT, miscellaneous signal pathways). The molecular profiles seem to depend on anatomic site, the mode of sun damage, and correlate with histologic patterns (e.g., BRAF mutations are common in “superficial spreading” melanomas arising in association with nevi of nonchronic sun-damaged skin, whereas they are rare in tumors of chronically sun-damaged skin or acral or mucosal sites with limited or no sun exposure; KIT mutations occur primarily in acral, mucosal lentiginous, and heavily pigmented melanomas). Molecular classification of melanomas is currently primarily of investigational value, but will likely play an increasing role for selecting patients for various treatment regimens targeting specific mutations.

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UNCOMMON VARIANTS OF MELANOMA A number of uncommon and unusual histologic variants of melanomas have been described. Separating them from conventional melanomas mainly serves to remind pathologists of the morphologic heterogeneity of melanomas and to point out diagnostic pitfalls.

SPINDLE CELL MELANOMA Melanomas with predominant spindle cell morphology comprise a spectrum of tumors (Fig. 12-66). If associated with a fibrous stroma throughout the invasive component, they are designated desmoplastic melanoma (DM). If intraneural and/or perineurial invasion is prominent and a neuroma-like growth pattern is present, the term neurotropic melanoma may be applied. Spindle cell melanoma (SCM) may be desmoplastic or neurotropic, both or none of the above (spindle cell melanoma, not otherwise specified). Some SCMs are heavily pigmented. Most of them, however, are amelanotic or paucimelanotic. The main diagnostic problem related to amelanotic SCMs is their potential confusion with various types of sarcoma or sarcomatoid carcinoma.

DESMOPLASTIC MELANOMA

Figure 12-66 Spindle cell melanoma. Nondesmoplastic spindle cell melanoma. the tumor is composed of atypical fusiform melanocytes without any significant intratumoral fibrosis.

indistinct. Not infrequently it manifests as a slightly erythematous nodule suspected to be a keloid or dermatofibroma (Fig. 12-67). Desmoplastic melanoma differs from conventional melanoma in its clinical course by a higher propensity for local cutaneous/subcutaneous recurrences and less frequent metastases to regional lymph nodes. Distant metastases typically appear first in the lung. Evidence has also emerged that desmoplasia may be a favorable prognostic finding, especially for patients with tumors measuring more than 4 mm in thickness.

CliniCal Findings deSMoPLAStic MeLAnoMA

Desmoplastic melanoma constitutes less than 4% of invasive melanomas. It typically occurs in the head and neck region of elderly individuals. However, DM may occur at any site, including mucosal sites, and may affect young adults. The clinical presentation is usually

uncoMMon vAriAntS oF cutAneouS MeLAnoMAS

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Spindle cell melanoma, not otherwise specified Desmoplastic melanoma (pure and mixed) Neurotropic melanoma Nevoid melanoma Spitzoid melanoma Blue nevus–like melanoma macrophage-rich melanoma Small cell melanoma rare tumors with peculiar morphologic features (e.g., signet ring cell, balloon cell, myxoid)

clinical Findings » Usually older patients, but may occur in younger individuals » Chronically sun-damaged skin of head and neck most often affected, but may occur anywhere, even mucosa » Frequent local recurrences » lymph nodes uncommonly involved histologic Features In situ melanoma: present in two thirds of cases (usually lentiginous pattern) » Invasive melanoma: » Usually amelanotic spindle cell phenotype » pure form: prominent stromal fibrosis throughout the majority of the tumor; usually paucicellular » Combined/mixed form: typical paucicellular fibrosing component associated with non-desmoplastic melanoma » Nerve involvement is common » patchy lymphocytic infiltrates are common » Cytologic atypia is variable; at least scattered hyperchromatic spindle cells are usually identified

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Figure 12-67 desmoplastic melanoma. a flesh-colored nodule is seen, which was clinically thought to be a keloid, but represented histologically a desmoplastic melanoma.

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Figure 12-69 desmoplastic melanoma. this Dm shows nodular fibrosing pattern. Clusters of lymphocytes are commonly seen in association with Dm.

Desmoplastic melanoma is characterized by the dispersion of usually amelanotic fusiform melanocytes in a prominent fibrous stroma, which gives the tumor a pink appearance at scanning magnification (Figs. 12-68 and 12-69). The associated in situ melanoma component typically displays a predominantly basilar lentiginous growth pattern (lentigo maligna). In approximately one third of the cases no associated in situ melanoma component can be detected. When DM is diagnosed, the majority of tumors have already invaded the reticular dermis. Extension into the subcutis with replacement of the fat by fibrous tissue is

common. Patchy lymphocytic aggregates and perineural or intraneural invasion are commonly associated with DM (see Fig. 12-69). In typical or pure DM, the histologic picture of a paucicellular fibrosing melanocytic tumors is present throughout the entire tumor (see Figs. 12-68 and 12-69). If fibrosis is only a partial and minor feature of an otherwise conventional melanoma, such tumors may be termed mixed or combined DM (Fig. 12-70). The degree of cytologic atypia of the tumor cells in a DM is variable. Melanocytes may be relatively bland, mimicking the appearance of fibroblasts or Schwann cells. However, usually at least scattered pleomorphic melanocytes with large hyperchromatic nuclei are present. At times pleomorphic cells predominate.

Figure 12-68 desmoplastic melanoma. Silhouette of a Dm shows a diffuse fibrosing process in the dermis and subcutis. there is associated in situ melanoma.

Figure 12-70 combined (mixed) desmoplastic melanoma. a solid melanoma nodule without intratumoral fibrosis is admixed with features of typical desmoplastic melanoma.

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diFFerential diagnosis Desmoplastic melanoma continues to be misdiagnosed and constitutes a significant part of medical malpractice claims related to melanoma. The most problematic diagnostic pitfall is to mistake a DM for a dermal scar or fibroma. It is prudent to perform immunohistochemistry for S-100 protein for any unusual or otherwise unexplained scarlike dermal spindle cell proliferation of chronically sun-damaged skin of the head and neck region (Fig. 12-71). Immunohistochemistry is also useful to assess and measure the extent of invasive DM in previously biopsied cases of lentigo maligna. Desmoplastic melanoma also should be distinguished from fibrosing (sclerosing) melanocytic nevi and nonmelanocytic tumors (dermatofibroma, neurofibroma, fibrosarcoma, sarcomatoid carcinoma, desmoplastic leiomyosarcoma). Desmoplastic melanoma differs from a sclerosing nevus by a number of features, such as associated in situ melanoma (if present), asymmetric silhouette, larger size, deep infiltration, presence of cytologic atypia and mitotic figures as well as the common association with patchy lymphocytic aggregates. Furthermore, DM is usually immunopositive only for S-100 protein, whereas desmoplastic nevi are often positive for A103

A

diFFerentiAL diAgnoSiS: ScLeroSing nevuS or deSMoPLAStic MeLAnoMA? Features Favoring Melanoma » Silhouette » asymmetry » Intraepidermal melanocytic proliferation » melanoma in situ » Dermal melanocytic proliferation » Ill-defined, diffusely infiltrative » hyperchromatic spindle cells » patchy lymphocytic aggregates » extension into subcutis » mitotic figures » Immunostaining » lack of staining for melan-a, gp100, tyrosinase, mItF » Increased labeling for Ki-67 Associated Features marked solar elastosis

»

and sometimes also HMB-45. Distinction of DM from nonmelanocytic tumors is usually readily achieved by strong and diffuse immunostaining of DM for S-100 protein.

B

Figure 12-71 desmoplastic melanoma. A, the tumor has an inflamed scarlike appearance. B, the tumor cells are positive for S-100 protein.

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NEUROTROPIC MELANOMA The term neurotropic melanoma (NM) refers to variants of invasive melanoma with frequent invasion of the perineurium and/or endoneurium of nerve trunks at the periphery of the main tumor mass (Fig. 12-72). Neurotropic melanomas are usually amelanotic. They may also show desmoplastic features (desmoplastic and neurotropic melanoma), but do not need to do so. Some NMs lack any or show only minimal intratumoral fibrosis. Neurotropic melanomas may show a traumatic neuroma–like pattern. On occasion an epithelioid cell melanoma shows prominent nerve involvement. A neurotropic spindle cell melanoma may be difficult to distinguish from a nerve sheath tumor (MPNST). Although both melanoma and MPNST are positive for S-100 protein, immunostaining for this marker may nonetheless be helpful. As a general rule, most MPNSTs stain only weakly and focally for S-100 protein, whereas most melanomas are strongly and diffusely S-100 protein positive. Anatomic location is also important. The majority of sporadic (i.e., outside of the clinical setting of neurofibromatosis occurring) malignant spindle cell tumors with schwannian features in the superficial soft

tissue of the head and neck region turn out to be melanomas, whereas deep soft tissue and paraspinal locations favor an MPNST.

NEVOID MELANOMA Nevoid melanoma is a small variant of nodular melanoma (Fig. 12-73). One may describe nevoid melanoma as a melanocytic proliferation, which at first glance mimics a nevus, but at close inspection is recognized as melanoma by the lack of maturation, and presence of mitoses and/or expansile aggregates of atypical melanocytes. Naturally there is a wide spectrum of lesions that are being designated as nevoid. The term nevoid melanoma serves to emphasize the diagnostic challenge or pitfall of recognizing small nodular melanomas arising in or mimicking a melanocytic nevus in the absence of a welldeveloped intraepidermal (in situ) melanoma component. There is no solid evidence to indicate that nevoid melanoma represents a prognostically distinct variant of melanoma. Tumors designated as nevoid melanoma tend to behave like other conventional invasive melanomas, if adjusted for various histologic prognostic parameters.

B

A

Figure 12-72 neurotropic melanoma. A, Spindle cell melanoma with plexiform growth pattern. B, Several nerve trunks at the periphery of the tumor are involved by melanoma.

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Dermatopathology

nevoid MeLAnoMA clinical Findings » Usually small papule (submitted as nevus, rule out atypia) histologic Features Nevuslike silhouette lack of obvious features of in situ melanoma Nested growth pattern loss/lack of maturation Focal expansile nests of melanocytes with atypia mitotic figures are usually found in dermal melanocytes thin elongated rete ridges

» » » » » » »

SPITZOID MELANOMA The term Spitzoid melanoma (Fig. 12-74) may be applied to melanomas with features of a Spitz’s nevus, such as the presence of large spindle and epithelioid melanocytes, associated epidermal hyperplasia, or rare Kamino bodies. It is currently unclear whether there is a distinct biologic behavior (perhaps a less aggressive clinical course) associated with Spitzoid features. Currently the designation of Spitzoid serves primarily to emphasize the diagnostic challenge of distinguishing a melanoma from a Spitz’s nevus.

B A

Figure 12-73 nevoid melanoma. A, the silhouette of the lesion is nevoid. there is no apparent intraepidermal melanoma. B, expansile aggregates of atypical epithelioid dermal melanocytes are present with mitotic figures.

A

B

Figure 12-74 Spitzoid melanoma. A, this melanoma shows a wedge-like silhouette with epidermal hyperplasia. Fascicles of pigmented spindle cells are present. there is focal loss of rete ridges. B, mitotic figures are present in dermal melanocytes. the patient died of metastatic melanoma. the tumor had originally been misdiagnosed as Spitz’s nevus.

Chapter 12

MELANOMA ARISING FROM OR SIMULATING BLUE NEVUS (SO-CALLED MALIGNANT BLUE NEVUS) Melanoma may arise in association with (Fig. 12-75) or mimic a blue nevus. Historically such lesions have been designated malignant blue nevus. Such melanomas are usually heavily pigmented and lack an intraepidermal component. This rare variant of melanoma can be diagnosed readily if a pleomorphic and mitotically active melanoma cell component with or without necrosis is immediately adjacent to a benign (usually cellular) blue nevus. Recognition of tumors with less atypia and without necrosis as malignant is more difficult. Malignant transformation of a cellular blue nevus is not uncommonly heralded by the emergence of sheets of epithelioid cells usually associated with an increased mitotic index. Rare cases exist, however, in which a reliable distinction between early melanoma and cellular blue nevus with atypical features cannot be made. Melanomas arising in association with blue nevi are usually detected at clinical stage II or higher and tend to behave aggressively. However, anecdotal experience suggests that some variants (tumors lacking necrosis and marked pleomorphism) exist, whose clinical course is akin to low- to intermediate-grade sarcomas characterized by repeated local subcutaneous recurrences with rare distant metastases, usually occurring late. While melanoma simulating blue nevus is usually thought of as a scenario in which a tumor mimics a cellular blue nevus, melanoma may also mimic on rare occasions the features of an epithelioid blue nevus. Epithelioid blue nevus–like melanoma is recognized by cytologic atypia, lack of maturation, absence of mature dendritic melanocytes, the presence of lymphocytic aggregates, and mitotic figures. A

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melanocytic proliferations

SMALL CELL MELANOMA Small cell variants of melanoma have been described that are histologically characterized by hyperchromatic cells with little or no cytoplasm (Fig. 12-76). The significance of this cytologic feature is uncertain. Most adult cases of melanoma with small tumor cells are associated with an obvious in situ melanoma component and do not pose a diagnostic problem. However, nodular small cell melanocytic tumors with many mitotic figures and apoptotic bodies that truly simulate a small cell malignant neoplasm, such as neuroendocrine carcinoma, lymphoma, Ewing’s sarcoma, or neuroblastoma do occur, but they are exceedingly rare. They may occur in children or adults. They have been associated with a more aggressive clinical course, but the evidence is anecdotal only. They are readily recognized as melanomas by immunoreactivity for S-100 protein. Small cell melanomas in children have also been referred to as melanoblastomas (see Fig. 12-76).

BALLOON CELL MELANOMA A peculiar histologic appearance of melanoma may be the presence of large epithelioid cells with abundant clear cytoplasm (Fig. 12-77). Primary balloon cell melanomas are usually recognized as such but may on rare occasion lead to confusion with other primary cutaneous clear cell tumors. Knowledge of this morphologic phenotype of balloon cells is primarily relevant for the differential diagnosis and workup of metastatic clear cell tumors (melanoma versus metastatic renal or adrenocortical carcinoma). There is no prognostic significance associated with balloon cell changes in primary or metastatic melanoma. B

Figure 12-75 Melanoma arising in association with a blue nevus. A, large nodules of melanocytes are present with focal necrosis and melanosis. B, the nodules are present in a background of blue nevus. a transition from ordinary to cellular blue nevus and melanoma with necrosis is seen.

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Dermatopathology

A

B

Figure 12-76 Small cell melanoma. A, Silhouette of a small cell melanoma arising in a congenital nevus. B, Small hyperchromatic melanocytes are present with numerous mitoses and individually necrotic cells. this melanoma occurred in a 4-year-old who developed lung metastases.

Figure 12-77 Balloon cell melanoma. melanoma with large pale epithelioid melanocytes (“balloon” cells).

SIGNET RING CELL MELANOMA Melanoma can also manifest with signet ring cell morphology (Fig. 12-78). This is of no prognostic significance, but relevant for the analysis of metastatic or mucosal signet ring cell tumors to bear in mind that melanoma needs to be considered in the differential diagnosis.

VERRUCOUS MELANOMA Some melanomas are associated with prominent papillomatous epidermal hyperplasia clinically simulating

Figure 12-78 Signet ring cell melanoma. melanoma with eccentric nuclei and cytoplasmic vacuole giving rise to a signet ring appearance.

verruca or seborrheic keratosis. Knowledge of this variant of melanoma is primarily relevant for clinicians to be aware of this clinical pitfall.

MELANOPHAGE-RICH MELANOMA Some melanomas are associated with numerous melanin pigment–laden macrophages giving the lesions a very dark appearance (Fig. 12-79). Historically some of these melanomas have been termed animal-type melanoma in reference to darkly pigmented melanocytic tumors in animals, such as in horses. We discourage the use of the term animal-type melanoma for a number of

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melanocytic proliferations

Figure 12-79 Melanophage-rich melanoma. primary metastasizing melanoma composed of heavily pigmented epithelioid melanoma cells admixed with many melanophages.

reasons. There is no solid evidence that melanophagerich melanomas behave differently from other melanomas if adjusted for other prognostic markers.

MELANOMA OF SOFT PARTS (CLEAR CELL SARCOMA) This tumor is commonly classified as sarcoma, but is discussed here because its tumor cells show evidence of melanocytic differentiation and the need to distinguish it from cutaneous melanoma.

CliniCal Findings As the name implies, this type of tumor with melanocytic differentiation arises in deep soft tissues closely associated with facial or tendoaponeurotic structures, but may extend into the subcutis or even dermis. It typically affects adolescents or young adults with a predilection for the distal extremities, but it may occur at many anatomic sites. The majority of patients eventually die of metastatic melanoma.

Figure 12-80 clear cell sarcoma. Nests and fascicles of melanoma cells are present in deep tendinous tissue.

Primary tumors usually lack marked pleomorphism. Melanoma of soft parts is immunohistochemically indistinguishable from cutaneous melanoma. It is typically positive for S-100 protein, gp 100, and Melan-A. Ultrastructurally melanosomes can be identified.

diFFerential diagnosis Melanoma of soft tissues or clear cell sarcoma can be confused with primary or metastatic cutaneous melanoma as well as cellular blue nevi. Its deep location and lack of an associated intraepithelial component are important for the distinction from primary cutaneous melanoma. Metastases from cutaneous melanoma are usually more pleomorphic than melanomas of soft tissue. If an unequivocal distinction is needed, molecular studies can be definitive. In contrast with cutaneous melanoma, melanoma of soft tissues are associated with a specific translocation, namely t(12;22)(q13;q13). The gene fusion product involves the EWS gene on chromosome 22 and the ATF1 gene.

MELANOCYTIC TUMORS OF UNCERTAIN MALIGNANT POTENTIAL/BORDERLINE LESIONS

HistologiC Features Nest and/or fascicles of tumor cells infiltrate deep soft tissues (Fig. 12-80). The tumor cells may be pale (clear cell features) or pink, fusiform or epithelioid in appearance. Multinucleate “wreath-type” giant cells are often seen at the periphery of the tumor.

Although the histologic assessment of melanocytic tumors by an experienced pathologist yields a reliable diagnosis in the majority of cases, there are occasional lesions in which it is best to acknowledge that one simply does not know for sure whether a tumor is a melanoma or not. There are different ways to express one’s uncertainty.

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Dermatopathology

Terms such as melanocytic tumor of uncertain malignant potential or borderline lesion are ways to paraphrase a pathologist’s inability to distinguish a nevus from melanoma. This is not necessarily a diagnostic failure from lack of experience or knowledge, but at times the most honest assessment of what can reliably be said about an unusual tumor by light microscopic analysis. Because the depth of experience varies (seeing a daily high volume is not necessarily as critical as getting follow-up on difficult cases) as well as one’s willingness to admit that one does not know, such cases are usually diagnostically controversial. When one faces diagnostic controversy and uncertainty, we advocate a pragmatic approach. A second opinion from a respected colleague is prudent practice. As long as melanoma cannot be excluded with certainty (i.e., several experienced pathologists consider melanoma), diagnostically controversial melanocytic tumors should be acknowledged as such, but excised completely. If sufficient tumor tissue is available for comparative genomic hybridization or fluorescence in situ hybridization studies, we recommend use of such ancillary techniques. If a number of chromosomal aberrations typical of melanoma are identified, a more compelling case can be made that a diagnostically problematic tumor is likely a malignant melanoma. Subsets of melanocytic tumors have been described, which at this point need to be considered as provisional categories, such as epithelioid melanocytoma or paraganglioma–like dermal melanocytic tumor. It is unclear from the rare reported cases whether those terms describe a truly new entity or a mix of unusual nevi and melanomas (epithelioid blue nevi and blue nevus–like melanomas in the case of epithelioid melanocytoma and amelanotic cellular blue nevus–like lesions versus primary nodular melanomas that have not metastasized in the case of paraganglioma–like dermal melanocytic tumor).

A

MELANOCYTIC PROLIFERATIONS ASSOCIATED WITH EPITHELIAL TUMORS On occasion a nevus or melanoma may arise intimately admixed with an epithelial tumor. This may be in the setting of a teratoma, neurocristic hamartoma (congenital nevus with heterologous elements), or a collision, such as with a seborrheic keratosis, squamous cell, or basal cell carcinoma. When a nevus or melanoma collides with another epithelial tumor, it may populate and colonize it. We regard squamomelanocytic and basomelanocytic tumors as histologic patterns which usually reflect a collision phenomenon, such as the collision of a cutaneous melanoma metastasis with a basal cell, carcinoma (Fig. 12-81). One must be careful not to overinterpret florid reactive pseudoepitheliomatous epidermal hyperplasia associated with melanoma as evidence of squamous cell carcinoma and melanoma.

METASTATIc MELANOMA Metastases occur in approximately one third of patients with primary invasive cutaneous melanoma. The pattern of spread is unpredictable. Any site of the body may be involved. Melanoma can spread to distant sites hematogenously as well as through lymphatic channels. The site of initial metastasis is of prognostic significance. Patients with regional lymph node metastasis who undergo lymphadenectomy have a 5-year survival rate ranging from 20% to 50%. The survival rare for patients presenting with distant metastases involving visceral sites is only 5%. Initial metastases to lymph

B

Figure 12-81 Basomelanocytic tumor. A, melanoma has metastasized to the site of basal cell carcinoma (collision phenomenon). B, an immunostain for gp100 (hmB-45) demonstrates that the basal cell carcinoma has been colonized by melanoma cells simulating the pattern of what has been referred to as basomelanocytic tumor.

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nodes, the skin and soft tissues are much more common than metastases to visceral sites. Metastases are generally divided into locoregional and distant metastases.

LOCOREGIONAL METASTASES (AJCC STAGE III DISEASE) Locoregional metastases include tumor deposits in lymph nodes draining the site of the primary tumor (Figs. 12-82 and 12-83) and metastases in the skin or soft tissue located between the primary tumor and the regional lymph node. Historically, the latter have been divided into satellite and in-transit metastases. Metastases confined to a defined radius, such as less than 2 cm from the primary tumor, were classified as satellites. If they were found farther away, they were designated in-transit tumors. Because biologically and prognostically satellite and in-transit metastases imply the same process, their distinction is arbitrary and unnecessary.

SENTINEL LYMPH NODE BIOPSY Sentinel lymph node (SLN) mapping and biopsy have become standard procedure in the United States and Australia for most patients with a primary cutaneous melanoma that is at least 1 mm thick. The procedure is also routinely offered to patients whose tumor measures slightly less than 1 mm in thickness, but is ulcerated and/or extends into the reticular dermis. The widespread use of SLN biopsy has been criticized because to

Figure 12-83 Melanoma metastatic to lymph node. Cytologically atypical and pigmented tumor cells are present.

date no overall survival benefit has been demonstrated and there is associated cost and risk for iatrogenic morbidity. Advocates of SLN biopsy argue that trials addressing potential therapeutic benefits are still ongoing and that the procedure at the very least provides powerful prognostic information. We see a role for SLN biopsy for patients willing to participate in clinical trials. In this context stratifying patients by risk for recurrence is critical. Otherwise differences in survival attributable to therapeutic intervention may not become apparent. Because the status of the SLN has been established as the most powerful predictor of outcome, its careful pathologic examination is important. For best results the SLN is to be bisected in the plane of the hilum along the longitudinal axis of the node. Most pathology laboratories examine multiple hematoxylin

B A

Figure 12-82 Melanoma metastatic to lymph node. A, Silhouette of a lymph node with nonpigmented metastatic tumor deposit. B, the tumor cells are immunoreactive for melan-a.

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Dermatopathology

and eosin (H&E)–stained sections and immunostains. In our experience, three H&E–stained sections and two immunostains (for S-100 protein and Melan-A/Mart-1 or gp100 [HMB-45]) suffice. More levels and more immunostains may yield additional rare cases of single cell metastases, but to date there is no evidence to suggest that results from a more extensive analysis justify the added time and cost. In fact evidence is emerging that only those metastases are clinically “relevant”; that is, of prognostic significance, which are detectable by routine hematoxylin and eosin stains. Contrary to initial hopes, results from additional step-sectioning or PCR-analysis for tyrosinase have not improved prognostic models. With the routine analysis of three H&E-stained sections and two immunostains, metastases are detected in SLNs in approximately 15% to 20% of patients. In our laboratory, we examine first one H&E-stained section. If it shows metastatic tumor (see Fig. 12-83), no further work-up is necessary. If it is negative, additional levels and immunostains are ordered. In most cases, immunopositive tumor has a clearcut histologic correlate on H&E–stained sections. Rare cases exist, however, in which single cell or micrometastases are only seen on immunostains. There are currently conflicting data about the significance of rare isolated immunoreactive tumor cells (after excluding a “false-positive” immunoresult because of technical issues).

DISTANT METASTASES (AJCC STAGE IV DISEASE) Any metastasis beyond the regional lymph nodes and the area drained by them is a distant metastasis, which include skin, soft tissue, distant lymph node and visceral

metastases. The site of initial metastasis affects prognosis. Patients presenting with nonvisceral metastases have longer survival than those with visceral tumor deposits. Among visceral metastases, evidence suggests that patients with pulmonary metastases live longer than those with other visceral metastases. Melanoma can metastasize to any site and in unexpected patterns. However, as a general rule it can be said that the most common first sites of visceral metastases are lung (15% to 20%), liver (15% to 20%), and brain (10% to 20%), followed by bone and intestine.

diFFerential diagnosis oF MetastatiC MelanoMa MetastatiC MelanoMa siMulating otHer neoPlasM

If a patient has a known primary melanoma and presents with a pigmented metastasis (see Fig. 12-81), the diagnosis of metastatic melanoma is straightforward. If the metastasis is amelanotic, the situation may be more challenging, because melanoma may assume a great variety of histologic appearances and mimic a number of primary or metastatic nonmelanocytic tumors, such as lymphoma, carcinoma, or sarcoma. In the absence of melanin pigment, immunohistochemical studies for melanocyte differentiation antigens are helpful. Immunostains may not be necessary, of course, if the primary tumor is available for review and the morphology of the invasive primary tumor and metastatic tumor deposit match. However, melanomas not infrequently show more pleomorphic features in metastases than detected in the primary tumor. Furthermore, some patients have other malignant tumors that may complicate the clinical situation and assessment of the origin of metastatic disease.

reAgentS For the iMMunohiStocheMicAL detection oF MeLAnocyteS Antigen

Antibody

Sensitivity

Specificity (for metastatic melanoma)

S-100 protein

anti-S100p

>95%

low

glycoprotein 100

hmB-45

75%

high

melan-a/mart-1

a103/m2-7C10

80%

high

tyrosinase

t311

80–90%

high

mItF

C5/D5

80–85%

Intermediate

Unknown

pNl2

85%

high

trp-1

ta99(mel-5)

90%

high

mItF, microphthalmia-associated transcription factor; trp, tyrosinase-related protein.

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diFFerentiAL diAgnoSiS: SPitZ’S nevuS or MeLAnoMA? Features Favoring Melanoma overall Silhouette » asymmetric » Intraepidermal melanocytic proliferation: » Ill-defined peripheral demarcation » predominance of solitary units of melanocytes over nests » Irregular and prominent pagetoid spread, especially at the edge » Confluence of nests along the dermal-epidermal junction dermal Melanocytic component lack of maturation Non-nevic growth pattern: oddly configured cellular aggregates, loss of nests, sheet-like aggregates » mitotic figures, especially in the deep portion of the lesion » atypical mitotic figures » Necrosis of melanocytes » marked nuclear atypia (large hyperchromatic nuclei) » “rhabdoid” features

» »

epiphenomena Ulceration marked effacement of rete ridges (consumption of the epidermis) lack of dull pink globules

» » »

When melanoma assumes an undifferentiated or unusual morphology, a major pitfall arises if melanoma is not being considered in the differential diagnosis, especially in the absence of a known primary melanoma. Such unusual amelanotic variants include spindle cell features (to be distinguished from sarcoma or sarcomatoid carcinoma), signet ring cell features (to be distinguished from adenocarcinoma), balloon or clear cell morphology (to be distinguished from renal cell or adrenocortical carci-

noma), and myxoid or giant cell features (to be distinguished from sarcomas). A panel of immunomarkers addressing possible alternative tumor types usually allows a definitive diagnosis. MetastatiC MelanoMa oF unknown PriMary tuMor

Approximately 5% to 10% of patients with metastatic melanoma present without a clinically apparent primary tumor (by history, clinical examination, and review of prior biopsies). Two thirds of them have metastatic disease in lymph nodes (especially in the axilla, groin, or neck). It is generally believed that this phenomenon is related to complete regression of a cutaneous melanoma. Before a diagnosis of unknown primary can be established, potential extracutaneous primary sites need to be excluded, such as the eye; oropharyngeal, nasopharyngeal, or anogenital mucosa; and soft tissue. In particular when melanoma manifest as metastatic disease in the liver, strong consideration should be given to a primary choroidal melanoma. The diagnosis of metastatic melanoma in the absence of a known primary is straightforward if the tumor is pigmented and occurs at a site, such as the lung or liver, where one would not expect a primary melanoma to occur. If a tumor is nonpigmented, immunohistochemical studies usually allow one to confirm the presence of a melanocytic differentiation. At most sites, such as the parenchyma of lymph nodes, brain, or lung, the metastatic nature of the disease is readily apparent. However, if a melanoma nodule occurs in the skin, squamous mucosa, soft tissue, or leptomeninges, the distinction of a primary from a metastatic tumor nodule can be difficult solely on morphologic grounds.

iMMunohiStocheMiStry For the diStinction oF MeLAnocytic tuMorS FroM hiStoLogic SiMuLAntS Marker

Melanoma

carcinoma

Sarcoma

Lymphoma

S100p

+

– or +1-

– or +2

–

t311/hmB45/m2-7C10

+

–

–

–

a103

+

– (+)

–

–

Cytokeratins

– (+)4

+

– or +5

–

lymphoid markers

–

–

–

+

muscle markers

– (+)6

– (+)7

– or +8

–

3

Some carcinomas, such as myoepithelial carcinomas, are positive for S100 protein. Follicular dendritic cell tumors are positive for S-100 protein; malignant nerve sheath tumors or alveolar soft part sarcomas may be positive for S100 protein. 3 adrenocortical carcinomas may be positive with a103. 4 Some melanomas express cytokeratins (e.g., Cam 5.2). 5 Some sarcomas, such as epithelioid sarcomas or angiosarcomas, express cytokeratins. 6 Some spindle cell melanomas may be positive for smooth muscle actinic and/or desmin. 7 muscle markers may be positive in some sarcomatoid carcinomas as well as in spindle cell melanomas. 8 muscle markers are positive in leiomyosarcomas or other myogenic/myofibroblastic sarcomas. 1 2

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Dermatopathology

PriMary Cutaneous MelanoMa versus MetastatiC MelanoMa to tHe skin

The distinction of primary from metastatic melanoma has obvious prognostic significance. If a large melanoma nodule is present in the subcutis with uniformly pleomorphic cells, numerous mitotic figures, and necrosis, one can assume the presence of metastatic disease if no associated nevus component is identified and the superficial dermis and epidermis are entirely normal without features

of regression or prior biopsy. A small deep dermal or subcutaneous melanoma nodule is also readily identified as metastatic (Fig. 12-84A), especially if lymphatic tumor emboli are identified. The situation is different with small superficial dermal melanoma nodules in close proximity to the epidermis (Fig. 12-84B), when a metastatic melanoma nodule mimics a nevus (Fig 12-84 C, D), or when the metastatic tumor also involves the epidermis (epidermotropic metastatic melanoma) (Fig. 12-85).

A

B

C D

Figure 12-84 Melanoma metastatic to skin. A, melanoma nodule in dermis/subcutis. B, Small superficial dermal melanoma nodule with collarette. c, metastatic melanoma simulating blue nevus. d, the blue nevus–like melanoma metastasis contains atypical epithelioid melanocytes.

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A

B

Figure 12-85 epidermotropic metastatic melanoma to skin. A, melanoma is present in the epidermis and dermis. the greatest horizontal dimension of the dermal component exceeds that of the intraepidermal melanoma. B, lymphatic tumor emboli are present.

A number of features need to be evaluated for the distinction of a primary melanoma from a superficial dermal metastasis. Solid evidence for a primary tumor is present if a melanoma nodule is associated with a precursor (a broad in situ melanoma component or melanocytic nevus). Although we have seen melanoma metastasize to the site of a nevus or melanoma biopsy, this is an exceedingly rare phenomenon. In general the presence of a precursor lesion is strong evidence in favor of a primary tumor. In the absence of a precursor lesion other parameters provide some guidance. Most metastases do not involve the overlying epidermis. If there is an intraepidermal component it is usually small. Its width

diFFerentiAL diAgnoSiS: PriMAry MeLAnoMA or derMAL MeLAnoMA MetAStASiS Features Favoring Primary Melanoma clinical Findings No history of prior melanoma history of longstanding lesion that has changed

» »

histologic Features major criteria » Intraepidermal melanoma extends beyond the perimeter of the dermal melanoma » associated melanocytic nevus » minor criteria » associated stromal changes (inflammation, fibrosis, features of regression) » low mitotic index » marked phenotypic heterogeneity of tumor cells » absence of lymphatic tumor emboli (much more commonly seen with metastatic lesion than in association with primary melanoma)

»

tends to be narrower than the greatest horizontal diameter of the dermal melanoma nodule (see Fig. 12-85). If the metastasis is very superficial, the overlying epidermis may be thinned and the tumor may be surrounded by an epidermal collarette. Lymphatic tumor emboli are more likely to be found in association with metastatic tumors than primary melanomas. At scanning magnification a dermal melanoma metastasis is suggested by a small, at times oddly shaped nodule of homogeneously atypical melanocytes. Mitotic figures tend to be more commonly seen in metastases than in primary tumors. Primary melanomas generally display more heterogeneity in the size and shape of nuclei and texture of the cytoplasm than metastatic tumors, which tend to be more uniform. There is typically more fibrosis and inflammation associated with primary tumors compared to metastases. These guidelines are not absolute. Clinical correlation is paramount. In the absence of a known prior melanoma one should hesitate to establish an unequivocal diagnosis of metastatic disease, if a superficial dermal melanoma nodule is found. All too often pathologists suggest metastatic disease, if they cannot identify in situ melanoma. Although the vast majority of primary melanomas arise at the dermal-epidermal junction, not all of them do. Some represent primary dermal melanomas. They may have developed from a dermal melanocytic nevus. PriMary MelanoMa oF soFt tissue versus MetastatiC MelanoMa to soFt tissue

Primary melanomas may arise in deep soft tissue. Melanoma of soft parts (clear cell sarcoma) was discussed earlier. When it occurs in the expected clinical setting (young patient, distal extremity), consideration is usually given to this diagnosis, especially if the tumor is found in association with deep tendinous tissue.

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Dermatopathology

A diagnostic problem typically arises when this tumor presents at an unusual site, such as the axilla, in which case it may be mistaken for metastatic melanoma. Metastatic melanomas are usually more pleomorphic than melanoma of soft parts. However, there is sufficient morphologic overlap that molecular studies are often needed for a definitive diagnosis. Other melanomas that may arise in soft tissue (usually subcutis) are those that are the result of malignant transformation of a deeply located blue nevus or congenital nevus. The presence of an associated benign melanocytic nevus component makes the primary nature of the tumor obvious. In the absence of a precursor lesion or on a partial biopsy, a definitive distinction may not be possible on histologic grounds alone. MelanoCytiC nevus versus nevoid Metastasis

Metastatic melanoma may not only be confused with primary melanoma but even with melanocytic nevi. Variants of dermal metastases have been described, which are difficult to distinguish from nevi, at least at scanning magnification. Such melanoma variants include blue nevus–like metastases that have been associated with cutaneous as well as choroidal melanoma. Metastatic melanoma simulating blue nevus should be considered, especially in a patient with a known primary pigmented melanoma, if a blue nevus–like proliferation appears suddenly and shows histologically unusual features, such as rare mitoses, epithelioid cell atypia, and associated inflammation. An immunostain for MIB-1 may be helpful to confirm the presence of an increased proliferative index. Ordinary blue nevi should be immunonegative. On rare occasions, small melanoma metastases may also mimic amelanotic epithelioid cell nevi. Fortunately the clinical setting (history of melanoma, sudden appearance

of multiple dermal nodules) usually strongly favors metastatic disease. nodal nevus versus MetastatiC MelanoMa

Benign nevomelanocytes may be present in lymph nodes (Fig. 12-86). They are usually small and confined to the fibrous tissue of the lymph node capsule and/or fibrous trabeculae traversing through the node. On very rare occasion a nodal nevus may occupy most of the fibrous tissue around and within a lymph node (Fig. 12-87). At times a nodal nevus may be present in the subcapsular sinus or lymph node parenchyma (Fig. 12-88). Nodal nevomelanocytes may be pigmented or amelanotic, epithelioid, or fusiform in appearance. Blue nevus variants, including cellular blue nevi, have been described (Fig. 12-86, B). Nodal nevi may be confused with metastatic melanoma, especially small microscopic subcapsular melanocyte aggregates in sentinel lymph nodes (Fig. 12-89). For the distinction of nodal nevi from metastatic melanoma, one needs to look at the location and cytology of the cells, and compare them to those of the primary invasive melanoma. Nevi are predominantly confined to fibrous tissue of the node. Small metastases are typically located in the subcapsular sinuses. However, exceptions exist. Melanoma metastases may be confined to the lymphatic channels of the lymph node capsule or be present in the center of a node. Rare nevi may involve subcapsular sinuses. On occasion a metastasis as well as a nodal nevus may be present (Fig. 12-90). After assessing the location of the melanocytes and their growth pattern within the lymph node, attention to cytologic features is important. Nodal nevomelanocytes are cytologically bland and lack mitotic figures, melanoma metastases tend to show cytologic atypia and mitoses. In difficult cases comparison of the nodal melanocytes with

A B

Figure 12-86 Melanocytic nevus in lymph node. A, Classic small nodal nevus with cytologically bland melanocytes in the lymph node capsule. B, Blue nevus involving lymph node capsule.

A

B

C

Figure 12-87 Large nodal melanocytic nevus in fibrous tissue and nodal parenchyma. Incidental large nevus found during an axillary node dissection in a patient with breast carcinoma. A, melanocytes are present in the capsule and extend into the nodal parenchyma. B, the melanocytes are cytologically bland; some are clustered around small vessels in fibrous trabeculae. c, an occasional nest of melanocytes is completely surrounded by lymphocytes.

A

B

Figure 12-88 Sentinel lymph node with intracapsular and subcapsular nodal nevomelanocytes. A, Cytologically bland small amelanotic epithelioid melanocytes are present in the capsule of a sentinel lymph node from a woman with breast cancer. Similar melanocytes are also present in the node beneath the capsule. B, another focus of intranodal melanocytes in the same node highlighted by an immunostain for mart-1.

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Dermatopathology

diFFerentiAL diAgnoSiS— nodAL nevuS or MetAStAtic MeLAnoMA? Features Favoring Melanoma Location of nodal Melanocyte Aggregates » Intraparenchymal or within lymphatic spaces cytology of tumor deposits atypia (enlarged nuclei with hyperchromatism or prominent nucleoli) » mitotic figures » Similarity to tumor cells of the primary tumor

»

immunophenotype Diffuse positive staining for gp100 mIB-1 labeling index greater than 2%

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the invasive tumor cells of the primary melanoma is recommended. Immunostains may also be of value. Nodal melanocytes tend to be negative for gp100, but focal staining may be seen. They are also negative for MIB-1, but positive for S-100 protein and Melan-A. Lack of staining for gp100, however, does not prove the presence of a nevus, because one third of melanoma metastases are negative for this antigen. Positive staining for S-100 protein and Melan-A only facilitates detection of melanocytes, but has no value in the distinction of a nevus from melanoma. If there is a question whether melanocytes are present in the fibrous trabeculae or lymph node parenchyma, a trichrome stain may help to recognize their location. Melanosis assoCiated witH MetastatiC MelanoMa

Metastatic melanoma may be associated with prominent intratumoral and/or peritumoral melanosis characterized

A

Figure 12-90 Sentinel lymph node with metastatic melanoma adjacent to a nodal nevus. a subcapsular melanoma metastasis is present as well as an intracapsular nevus component.

by dense collections of melanophages in soft tissue. This is most often seen in partly necrotic melanoma and likely caused by release of melanin pigment from dying tumor cells, but can also occur in association with small dermal melanoma metastases. Prominent peritumoral melanosis may pose a diagnostic pitfall if a biopsy samples only melanophages and fails to capture viable tumor cells. Diffuse cutaneous or generalized melanosis is a rare complication of end-stage metastatic melanoma. It is clinically characterized by slate blue to gray discoloration of the skin. Histologically there is increased melanin pigment deposition in the dermis and subcutis, primarily in macrophages, but it can also be found in other cells, such as fibroblasts or as free melanin. There may or may not be hyperpigmentation of the overlying epidermis.

B

Figure 12-89 Sentinel lymph node with a small subcapsular nodal nevus. A, Cytologically bland amelanotic small epithelioid melanocytes are present beneath the lymph node capsule. B, their cytology differs markedly from the atypical pigmented large epithelioid melanocytes of the patient’s primary invasive melanoma.

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melanocytic proliferations

anCillary studies iMMunoHistoCHeMistry

Immunohistochemistry (IHC) is currently the main ancillary technique of proven clinical value for the diagnosis of melanocytic tumors. IHC aids in the distinction of amelanotic primary or metastatic melanocytic tumors from non-melanocytic mimics. It also facilitates the recognition of microscopic deposits of melanocytes in lymph nodes. Furthermore, IHC can help better visualize the density and growth pattern of primary melanocytic tumors when melanocytes are poorly visible because of suboptimal histology or dense inflammation. A number of reagents are currently available for the detection of proteins associated with melanocyte differentiation. They include monoclonal antibodies HMB-45 (to detect glycoprotein 100), A103 (to detect melan-A), M2-7C10 (to detect Mart-1), T311 (to detect tyrosinase), D5 (to detect microphthalmia-associated transcription factor), and PNL2 (to detect a yet not fully characterized melanoma antigen). A positive reaction with these antibodies leads to cytoplasmic staining of melanocytes, except for D5. A positive result for microphthalmia-associated transcription factor is obtained once nuclear staining is observed. For primary melanomas, antibodies for melanA/Mart-1 are helpful for the distinction of amelanotic epithelioid nodular melanoma from poorly differentiated carcinoma or epithelioid sarcoma. For spindle cell melanomas, especially desmoplastic melanoma, anti-S100 P remains the most important marker for diagnosis. Antibodies against nerve growth factor receptor may sometimes add value. For the detection of metastatic tumors, S-100 protein has the greatest sensitivity. Primary cutaneous or metastatic tumors that are histologically compatible with melanoma and strongly immunoreactive for anti-S100P while negative for epithelial, myoepithelial, or dendritic cell markers should be regarded as melanoma. If the tumor is also positive for one or more of the melanocyte differentiation antigens, the melanocytic origin is certain. On the other hand, positive staining for melanocyte differentiation antigens does not always imply that the tumor is a bonafide melanocytic tumor. Positive staining with A103, for example, may be seen in adrenocortical tumors. Positive staining for miscellaneous melanocytic markers is often found in angiomyolipomas or other related tumors (perivascular epithelioid cell tumors, aka as PEComas). Occasionally, a patient with a history of melanoma develops a pleomorphic tumor morphologically compatible with melanoma that is negative for S100 protein and any other melanocyte marker. Although the rare possibility of a second malignancy (e.g., undifferentiated sarcoma) needs to be considered, more often than not, such tumors represent undifferentiated metastatic melanoma, especially, if present within a lymph node. Other synchronous or metachronous metastatic lesions in such patients may

display focal bonafide melanocytic differentiation. With rare exceptions, such as the distinction of a sclerosing nevus from desmoplastic melanoma, there is currently no good reason for using IHC for melanocyte differentiation markers for the distinction of nevus from melanoma because of overlapping antigen profiles. Some pathologists use the labeling index and staining pattern for the proliferation marker Ki-67 for the distinction of nevus from melanoma. Although it is generally true that a significantly increased labeling index favors melanoma, such findings need to be placed in the proper histologic context to avoid a diagnostic error. Proliferative nodules or growing nevi, for example, show mitotic figures and an increased expression of Ki-67, but are benign. Furthermore, some melanomas grow slowly and may display a labeling index for Ki-67 of less than 5%. MoleCular studies

Cytogenetic studies (CGH, FISH) or PCR-based studies can be helpful for the distinction of atypical nevi from melanoma or the distinction of cutaneous melanoma from melanoma of soft parts (aka clear cell sarcoma), or metastatic uveal melanoma. Melanoma of soft parts carries a characteristic translocation [t(12;22)] not seen in cutaneous or uveal melanoma. Uveal melanoma, in contrast with other types of melanoma, commonly shows monosomy 3. Many uveal melanomas also carry somatic mutations in the heterotrimeric G protein a-subunit, GNAQ. A recently developed FISH assay using probes to loci on chromosomes 6 (RREB1 on 6p25, MYB on 6q23) and 11 (cyclin D1 on 11q13) shows promise to help in the distinction of nevi from melanoma. Preliminary data suggest a sensitivity of around 85%. A positive test (detecting a number of chromosomal gains or losses above a threshold level) strongly supports the diagnosis of melanoma, but does not represent unequivocal proof of malignancy (“false-positive” test results may occur). A negative result does not exclude melanoma, but makes it less likely. Molecular studies for certain mutations, in particular BRAF and KIT mutations may also help for treatment decisions by selecting patients with tumors most likely to respond to target therapy. Fontana stain

While the Fontana stain still has value for the evaluation of primary pigmentary disorders, it is currently rarely used for the diagnosis of melanoma. IHC is more sensitive. eleCtron MiCrosCoPy

Historically, electron microscopy has been useful to detect melanosomes as evidence of melanocyte differentiation of amelanotic tumors. However, the advent of IHC and availability of numerous melanocyte markers for melanocyte differentiation has largely rendered electron microscopy irrelevant (and too costly) for the evaluation of melanocytic tumors.

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Dermatopathology

PATHOLOGY REPORTING OF MELANOMA PRIMARY CUTANEOUS MELANOMA A pathology report of melanoma should clearly state the diagnosis, identify the patient and site of involvement by melanoma, and document the status of the margins. If melanoma is limited to the epidermis, it should be specified as in situ melanoma. If melanoma is invasive, as a minimum, the features needed for staging the tumor (thickness, Clark level for tumors measuring 1 mm or less in thickness, the presence or absence of ulceration and satellites) should be listed. The reporting of additional features is encouraged, but in our opinion not necessary. Their recording currently serves mainly academic purposes. If there are prominent features of regression associated with intraepidermal melanoma or the area of the dermis involved by regression is thicker that the residual invasive tumor, documentation of this finding and measurement of the area of regression may be beneficial for risk assessment and clinical management. If, for example, in situ melanoma is associated with regression, one cannot entirely rule out potential for recurrence, although it may be very small.

METASTATIC MELANOMA In addition to the usual patient identifiers, the pathology report should specify the anatomic site as well as

tissue type (e.g., lymph node, brain, subcutaneous adipose tissue) involved by melanoma. If a regional lymph node is positive for melanoma, the current AJCC staging system requires documentation on whether or not metastatic melanoma extends into extranodal soft tissue. One may also comment on the tumor volume (rare solitary melanocytes versus bulky intranodal tumor deposits). Studies are currently underway to evaluate how this information can best be standardized and what its relevance might be for clinicians with regard to their decision whether or not to remove additional nodes. When several lymph nodes are removed, the total number of positive nodes and negative nodes should be reported.

PROGNOSIS The prognosis of a patient affected by melanoma depends on the clinical stage.

CliniCal stages i and ii For those with localized primary melanoma, the histologic features of the primary melanoma, in particular tumor thickness, presence of ulceration, tumor mitotic rate, and level of invasion are relevant parameters to assess a patient’s risk for recurrence. Host factors such as age and immunocompetence are also important.

MeLAnoMA StAging clinical Stage

Pathologic Findings

5-year Survival rate (%)

0

melanoma in situ

Ia

thickness: <1 mm; Clark level: II or III; no ulceration

100 ≥95

IB

thickness: <1 mm, but Clark level IV or V and/or ulcerated thickness: 1.01–2 mm, nonulcerated

89–91

IIa

thickness: 1.01–2 mm, ulcerated thickness: 2.01–4 mm, nonulcerated

77–79

IIB

thickness: 2.01–4 mm, ulcerated thickness: 4 mm or more, nonulcerated

63–67

IIC

thickness: >4 mm, ulcerated

45

III

regional lymph node metastasis*

25–70

IV

Distant skin, subcutaneous, or nodal metastases or visceral metastases

<20

*Subcategories IIIa, B, and C exist. Within stage III, the prognosis is best for nodal micrometastasis (metastasis detected only by microscopic examination) associated with a nonulcerated primary tumor (IIIa). It is worst for patients with multiple positive nodes, grossly positive nodes, extension of metastatic tumor into extranodal soft tissue, and satellites. adapted and modified from Balch Cm, Buzaid aC, Soon SJ, et al.: Sentinel lymph node biopsy for cutaneous melanoma: the Stanford experience, 1997-2004. Semin Surg Oncol 2003;21:43-52.

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Patients with thin primaries (Breslow thickness less than 1 mm) have an estimated 5-year survival rate of 90% to 95%, depending on the presence or absence of histologic ulceration and a Clark level of greater than III. The 5-year survival rate for patients with intermediate-thickness melanoma (1.01 to 4 mm) is 60% to 90%. It is 65% to 70% for a more than 4-mm thick primary without ulceration and approximately 45%, if the tumor is ulcerated.

CliniCal stage iii Regional lymph node metastasis is associated with a 5-year survival rate of 13% to 69%. The odds for survival depend on the number of nodes involved and extent of disease (micrometastasis versus macrometastasis). Regional cutaneous or soft tissue metastases (also known as in-transit or satellite lesions) are associated with a 30% to 50% 5-year survival rate. The prognosis is worse (reduced 10% to 30% 5-year survival), if both regional cutaneous and nodal metastases are present.

SURGICAL MANAGEMENT BioPsy/exCisions oF MelanoCytiC nevi Although shave biopsies are suitable for small pigmented lesions, especially if located in the face or if the suspicion for melanoma is low, they are to be discouraged for large and clinically complex-appearing lesions. Although in many cases a definitive diagnosis can be made on a shave biopsy, partial small tissue sampling carries the risk of sampling errors as well as suboptimal diagnostic evaluation because of the fact that important histologic parameters, such as symmetry or circumscription of the peripheral border of a lesion, cannot be evaluated. Once a melanocytic nevus is diagnosed histologically, it does not need to be excised except for specific requests by patients for cosmetic reasons or concerns about its biology; for example, if the diagnosis is not entirely certain because of sampling issues (too small a biopsy to distinguish nevus from melanoma) or for other reasons (unusual morphology that is difficult to interpret). Margins for such excisions may be as narrow as possible.

PriMary MelanoMa CliniCal stage iv The prognosis for distant metastatic disease is generally poor, with 5-year survival rates of less than 20%. The prognosis depends on the number and site of metastases as well as on host factors.

Malignant melanomas should be completely excised surgically. Recommendations for the optimal width of an excision for a primary cutaneous melanoma (see Fig. 12-91) should be viewed as guidelines not as dogmatic rules. They have been revised repeatedly at various times with a trend toward more conservative surgery.

Diagnosis of Melanoma

Melanoma in situ

1 mm thick

1 mm thick and  Clark level IV or ulceration

1.01-2.0 mm thick

0.5 cm margin

1.0 cm margin

1.0 cm margin

1.0-2.0 cm margin

Surveillance

Consider SLN biopsy

2.01-4.0 mm thick

4.0 mm thick

2.0 cm margin

Figure 12-91 treatment algorithm for primary cutaneous melanoma.

498 Current guidelines recommend a 5-mm margin for in situ melanoma and at least a 1-cm margin for normal skin for invasive melanoma. On occasion a compromise must be made for the benefit of the patient. The desire for a textbook margin should be weighed against the potential harm from tissue loss for the patient in a cosmetically sensitive area. A narrow margin is acceptable at times. For a patient with a melanoma near the eyelid, for example, a suboptimal margin may be preferable to potential complications or disfiguring from wider surgery. A number of dermatologic surgeons attempt to excise primary melanomas, especially of the lentigo maligna type, using frozen section for margin assessment. We discourage the use of frozen sections for margin controls of melanocytic tumors, because of the inherent difficulty of interpreting frozen section material. However, in exceptional circumstances, especially in a laboratory that can produce high-quality frozen sections, frozen section analysis may be appropriate or prudent, such as for margin control in the region of the facial nerve, to avoid increased risk of nerve injury from a second operation at that site.

sentinel lyMPH node MaPPing and BioPsy Sentinel lymph node mapping and biopsy are currently routinely performed as a staging procedure for most patients with a primary melanoma of AJCC 2002 stage pT1B or higher (i.e., the melanoma measures at least 1 mm in thickness or more or, if the thickness is less than 1 mm, the melanoma extends to Clark level IV or is ulcerated), but less than pT4. Sentinel lymph node biopsy may also be performed on patients with thin or thick melanomas (pT1A or PT4), but this practice is controversial.

ManageMent oF MetastatiC MelanoMa The role of surgery in the management of metastatic melanoma is primarily to obtain tissue for diagnostic and staging purposes, to relieve tumor burden, and/or to assess treatment responses.

Dermatopathology

NONSURGICAL TREATMENT OPTIONS Various nonsurgical therapies are being offered for primary and metastatic lesions of melanoma. Topical agents, such as imiquimod or radiation, may be used for the management of lentigo maligns, when surgery may not make sense (e.g., comorbidity). Radiation may also be used for primary or locally persistent melanomas, when a negative surgical margin cannot be achieved, especially in the head and neck region. Medical treatments of metastatic melanoma to date have for the most part been disappointingly ineffective. Single or multiagent chemotherapy may produce responses from 5% to 30%. The combination of chemotherapy with immunomodulators, such as IL-2, which is also referred to as biochemotherapy, may yield a slightly better response. However, the impact of most current treatment regimens on overall survival has been marginal. With the discovery of distinct mutations associated with various melanomas, such as KIT mutations in mucosal or acral melanoma, a number of trials are currently underway to explore the use of small molecules for targeted therapy. Various vaccine trials also being pursued. Targeted therapy and novel immunologic approaches currently hold the greatest promise for improvements in the medical treatment of patients with metastatic melanoma. SuggeSted Further reAding ackermann aB, massi D, Nielsen t. Dysplastic nevus. philadelphia: ardor Scribendi; 1999. Balch Cm, Buzaid aC, Soon SJ, et al. Sentinel lymph node biopsy for cutaneous melanoma. the Stanford experience, 1997-2004. Semin Surg Oncol. 2003;21:43–52. Balch Cm, houghton aN, Sober aJ, Soong S-J. Cutaneous melanoma. St. louis: Quality medical publishing; 1998. Barnhill rl, piepkorn m, Busam KJ. Pathology of melanocytic nevi and malignant melanoma. 2nd ed. New york: Springer; 2004. Cochran aJ, Bailly C, paul e, remotti F. Melanocytic tumors. A guide to diagnosis. philadelphia: lippincott raven; 1997. Crowson aN, magro Cm, mihm mC. The melanocytic proliferations. A comprehensive textbook of pigmented lesions. New york: Wiley-liss; 2001. massi g, leBoit p. Histologic diagnosis of nevi and melanoma. Darmstadt: Steinkopff Verlag; 2004. mooi WJ, Krausz t. Biopsy pathology of melanocytic disorders. london: Chapman & hall medical; 1992. Swetter Sm. malignant melanoma. http://emedicine.medscape.com/ article/1100753-overview; 2008. thompson JF, Scolyer ra, Uren rF. Surgical management of primary cutaneous melanoma: excision margins and the role of sentinel lymph node examination. Surg Oncol Clin North Am. 2006;15:301–318.