Dermal Melanocytoses

and Victor G. Prieto2



(1)
Division of Dermatopathology, Miraca Life Sciences, Dallas, TX, USA

(2)
MD Anderson Cancer Center, University of Texas, Houston, TX, USA

 




Nevus of Ota and Ito



Clinical Features


Nevus of Ota : Also known as oculodermal melanocytosis or nevus fuscoceruleus opththalmomaxillaris , it presents as a diffuse, slightly speckled, unilateral macular lesion of bluish to dark-brown pigmentation of the skin in the area of the ophthalmic and maxillary divisions of the trigeminal nerve. The conjunctiva and sclera can be involved in more than half of the cases and occasionally the mucous membranes of the nose, ear, and oral cavity. Nevus of Ota can be bilateral in up to 10 % of cases [1, 2]. Other affected areas include the forehead, the temple, the cheeks, and the nose. The cutaneous and mucosal discolorations in nevus of Ota are present throughout life and do not usually fade away with time; however, color can vary in intensity. These lesions are most commonly seen in Asians and in darker-skinned individuals and are uncommon in white patients. Most nevi of Ota present at birth (60 % of cases) and the second peak is seen during adolescence with a female predominance (4:1 ratio). Rare acquired cases with adult onset are sometimes considered as a separate disease, such as Hori nevus (acquired bilateral nevus of Ota-like facial macules). Malignant degeneration in a nevus of Ota is extremely rare [36]. The choroid is the most common site affected, but the uvea, iris, and optical tract can also be involved. Although nevus of Ota is much more prevalent in Asians, malignant change appears to be much more common in white patients [5, 6]. Nevus of Ota can be associated with meningeal melanocytosis, Sturge-Weber disease, Klippel-Trenaunay syndrome, and spinocerebellar degeneration.

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Fig. 2.1
Nevus of Ota. Note the very subtle population of dendritic melanocytes in superficial and reticular dermis depicted in this image (a). These changes can be overlooked easily if adequate clinical information is not provided (b). Higher magnification shows the elongated and pigmented dendritic melanocytes (c, d)

Nevus of Ito : Also known as nevus fuscoceruleus acromiodeltoideus , it is a very rare dermal melanocytosis that clinically is characterized by heavy macular pigmentation in the distribution of the posterior supraclavicular and lateral brachial cutaneous nerves (shoulders and upper back). Nevus of Ito differs from the nevus of Ota only by its area of distribution and lower incidence. Clinically, it presents as a subtle, light gray, mottled, macular pigmentation. Similar to nevus of Ota, lesions do not regress with time. These lesions more commonly appear in the first to second decades of life, but are possibly congenital in nature. Nevus of Ito often occurs in association with nevus of Ota in almost half of patients [7]. Also, rarely can melanoma develop [8].


“Mongolian” Blue Spot



Clinical Features


“Mongolian” spot was the old terminology used for blue-gray macules and patches frequently located on the sacral region (including gluteal and lumbar regions). These lesions should be named “blue nevi” or “dermal melanocytoma.” Some lesions can be occasionally found at extra-sacral locations, including posterior thighs, legs, thorax, back, and shoulders [9]. Most lesions are a few centimeters in diameter (3–5 cm), but in some patients, they are large enough to cover the entire lower back and buttocks (>10 cm in diameter). They usually are present at birth or soon afterward and are most commonly seen in Japanese, Chinese, and dark-skinned individuals (more common in males). Most lesions undergo spontaneous regression during infancy or childhood and generally disappear by puberty (in contrast with nevus of Ito and Ota, which do not regress). Persistence of the lesion into adulthood is rare and has been associated primarily with extra-sacral locations. These lesions have not been associated with melanoma. They can be a marker of an underlying storage disease, such as Hurler syndrome, GM1 type I gangliosidosis, and mucolipidosis type I [1012]. The coexistence of widespread capillary malformations (nevus flammeus) along with this type of blue nevi, nevus spilus, nevus of Ota, and nevus anemicus is referred as phacomatosis pigmentovascularis [13].

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Fig. 2.2
Mongolian spot. The lesion illustrates the rare dendritic melanocytes in the dermis (very scarce) (a). Higher magnification showing the rare dendritic cells interspersed among the collagen bundles (b, c)


Nevus of Sun and Nevus of Hori



Clinical Features


Nevus of Sun, also known as nevus fuscoceruleus zygomaticus , is a rare melanocytosis that represents an acquired form of nevus of Ota. Nevus of Hori is a rare acquired bilateral nevus similar to a nevus of Ota. Nevus of Sun has a similar distribution as nevus of Ota; however it is more commonly located in the zygomatic branch area. Nevus of Sun, contrary to nevus of Ota, never involves the eye and never is congenital. Hori nevus presents as bilateral and symmetrical bluish macules in the malar region of the cheek but also can affect the forehead, temples, and nose. Both of these melanocytoses exclusively affect Asians and there is a predilection for females [14]. Malignant degeneration has not been described.


Histopathology


The histologic changes in these melanocytoses are very similar. In the papillary and upper reticular dermis, there is a band-like distribution of isolated, pigmented, spindled, bipolar, or dendritic melanocytes surrounded by fibrous sheaths. These pigmented dendritic cells are very similar in morphology to those observed in blue nevi. Thus they have oval nuclei with fine and evenly distributed chromatin with inconspicuous nucleoli. The cytoplasm has characteristic long and thin dendrites speckled with fine granules of melanin. These spindle cells are evenly distributed throughout the dermis with occasional crowding around adnexal and/or neurovascular structures. In some instances these cells can involve the deep dermis and subcutaneous fat. Dermal melanophages associated with dendritic cells are uncommon (as opposed to blue nevi). In most cases, the melanocytes are separated from each other without formation of cellular aggregates ; however, rarely can they conglomerate in a pattern similar to a blue nevus. In some occasions these melanocytes can be scarce and thus special stains (Fontana Masson) can be of help.

In cases of nevus of Ota and Ito, the melanocytes are commonly located in superficial dermis in contrast to other melanocytoses . Also, in nevus of Ota and Ito, there is epidermal hyperpigmentation and normal to focally increased numbers of intraepidermal melanocytes without forming a junctional component.


Differential Diagnosis


Sometimes these dermal melanocytoses can show inconspicuous histology; thus, if the clinical picture of a pigmented lesion is unknown to the pathologist, the histopathology can be easily overlooked. The clinical presentation is more obvious than the histological one, and when in doubt, immunostains for melanocytic antigens (MART-1, gp100 [HMB-45]) or special stains (Fontana Masson) can be very helpful to highlight the dendritic melanocytes. In addition, in cases where the lesions are aberrantly located, the histology can be missed and sometimes confused with normal skin. Also, cases of exogenous or endogenous dermal hyperpigmentation (from hemosiderin deposition) can look very similar to dermal melanocytoses; however, if one looks closely, the hemosiderin pigmentation should be located within macrophages and not within melanocytes. In cases in which the distinction is problematic, special stains can be handy as hemosiderin will be highlighted with iron stains (Perl stains), such as in minocyclin pigmentation.


Blue Nevus



Clinical Features


Blue nevus is a common benign dermal dendritic melanocytic proliferation that was first described by Jadassohn-Tièche in 1906. These nevi most commonly arise in children and young adults (more common in females) but can occur at any age or can present as congenital lesions. Common locations are the dorsal aspects of the hands and feet (most common location), head and neck, and trunk and buttocks [15]. Rarely have they been described in extracutaneous locations, such as the subungual region, the orbit and conjunctiva, oral cavity, sinonasal mucosa, meninges, and internal organs [1620]. When they present as congenital lesions, they are usually found on the scalp; however, other sites can also be involved such as the thorax and distal extremities [21]. Many different clinical forms of blue nevi have been reported; the most frequent consists of a well-demarcated, slightly raised papule, often <1 cm in diameter, ranging in color from blue/gray to black. Blue nevi more commonly affect dark-skinned adolescent or adult females. Lesions usually remain static throughout life but may undergo change in color and gradual involution. Congenital lesions present as large nodules that involve the deep dermis and in some occasions the subcutaneous fat; these lesions remain stable until adolescence then gradually enlarge.

Rarely may multiple blue nevi occur in a familial setting. They may be associated with LAMB syndrome (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi), NAME syndrome (atrial myxomas, myxoid neurofibromas, ephelides), or present sporadically in a diffuse distribution or grouped in a circumscribed anatomic area (so-called agminated blue nevi ) [22, 23].

Blue nevi may rarely involve the lymph nodes, usually in the capsular region, sometimes with an extension into perinodal adipose tissue. Their distinction from metastatic melanoma may be problematic, particularly in sentinel lymph node specimens [24, 25]. In contrast with metastatic melanoma, nodal blue nevi are located in the fibrous capsule of the lymph node and are composed of a combination of subtle elongated spindle cells with dendritic processes and pigment-laden melanophages and histologically resemble their cutaneous counterparts [26, 27].


Histopathology


Blue nevi are composed by a somewhat symmetrical upper and/or mid-dermal proliferation of bipolar, spindle-shaped cells, sometimes arranged in short fascicles. The melanocytes show elongated and slender dendritic processes and contain variable amounts of melanin pigment in their cytoplasm. Their nuclei are small, elongated, and hyperchromatic. Cellular atypia is minimal and mitotic figures are almost never seen. Most blue nevi are relatively small and located within the superficial dermis; however, they may extend deep into reticular dermis along adnexal structures, arrector pili muscle, and/or neurovascular structures (~perineural invasion, an occasional pitfall in the interpretation of this lesions). These dendritic melanocytes are frequently arranged around hair follicles in a densely cellular sheath of cells and often separated from the follicular epithelium by a thin rim of collagen. The involved hair follicles are frequently dysmorphic and undergo atrophy and in some cases may be entirely replaced by bundles of pigmented melanocytes. The dendritic melanocytes are associated with some degree of stromal fibroplasia, sclerosis, and scattered melanophages; however, the neoplastic cells do not alter the normal dermal architecture and distribution of skin adnexa. Not uncommonly, the dendritic cells seen in blue nevi are intermixed with oval and spindle melanocytes reminiscent of type B or type C (neurotized) melanocytes. The maturation gradient in blue nevi is absent since all the neoplastic cells within the lesion are similar; thus, there is no zoning/maturation pattern. In most cases, there is a grenz zone of uninvolved papillary dermis that separate the lesion from the overlying epidermis. The overlying epidermis lacks a junctional component, unless when blue nevi are part of a combined nevus (see below) [28]. Also, it is not unusual to observe hyperpigmentation of the basal layer of the epidermis and mild melanocytic hyperplasia along the epidermis and the follicular infundibulum. Some lesions may show intermediate histologic features between a nevus with congenital pattern and common (or cellular) blue nevus; such lesions can be designated as combined nevus with intradermal nevus with congenital pattern and blue nevus.

While most of blue nevi are stable lesions, over time the dendritic and spindle/oval melanocytes tend to decrease in number and the collagen production is more pronounced. In more advanced stages, the dendritic cells are localized in the periphery of the lesion, and in the center the oval cells are intermixed with thickened collagen bundles. In the final stages of blue nevi, the lesion may be almost entirely replaced by dense compact collagen with melanin interspersed between the collagen bundles , either lying free or within macrophages (sclerotic blue nevi).


Differential Diagnosis


Blue nevi depicting classical histomorphological features are not usually difficult to diagnose and most of the time are accurately interpreted. However, certain histologic variants such as amelanotic (hypopigmented) blue nevi may appear similar to other spindle cell proliferations, such as dermatofibroma (see below). Immunohistochemistry usually clarifies the diagnosis in morphologically equivocal lesions. Sclerosing blue nevi may resemble desmoplastic melanoma or other dermal spindle cell proliferations, but can be distinguished by its negligible cytologic atypia and the characteristically diffuse expression of HMB45 antigen and usually S-100p expression, which is different from desmoplastic melanoma (see below) [2931]. Another important differential diagnosis is a subtype of metastatic melanoma to the skin that mimics blue nevus due to the dendritic morphology of the tumor cells. However, this rare form of metastatic melanoma typically displays severe cytologic atypia and mitotic figures are easily found [32].


Immunohistochemistry and Molecular Findings


By immunohistochemistry the cells of blue nevi are positive for S100p, MART-1, and HMB-45 antigen; however, the intensity of the labeling is highly variable. Many nevi and melanomas show oncogenic mutations in signaling components of the mitogen-activated protein kinase pathway, in particular BRAF and NRAS. However, blue nevi less frequently exhibit mutations in these pathways, with BRAF mutations reported in 12 %, NRAS in 11 %, GNA11 in 7 %, and KRAS in 11 % of lesions [33, 34]. Recent studies reveal an increased frequency of somatic mutations of heterotrimeric G-protein α subunit (GNAQ) in up to 83 % of blue nevi. In addition, GNAQ or GNA11 mutations have been found in uveal melanomas (46 %) as well as in blue nevus-like melanoma (50 %) [35]. These findings support the interpretation that blue nevi and variants represent a distinct type of melanocytic neoplasms.

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Fig. 2.3
Conventional blue nevus. The lesion depicts a small and symmetric proliferation of dendritic melanocytes occupying reticular dermis (a). Dendritic melanocytes arranged around hair follicles and the overlying epidermis lack a junctional component (b). Note the increased number of dendritic melanocytes interspersed among the thickened collagen fibers (c). Higher magnification shows the bipolar melanocytes with elongated dendritic processes containing cytoplasmic melanin pigment, along with scattered melanophages (d)


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Fig. 2.4
Conventional blue nevus. This image depicts a small pigmented papule in the dermis with banal appearance. Note the abundant and evenly distributed pigment in the lesion (a). Note the propensity of dendritic cells to surround hair follicles (b). The cells are elongated and the cytological details have been partly obscured by the abundant pigment (c). Higher magnification displays the bipolar dendritic melanocytes associated with stromal fibroplasia (d)


Histologic Variants of Blue Nevus



Combined Blue Nevus


Combined nevi are composed of more than one nevus type in a single lesion. They may be composed of any combination of common acquired nevi, blue nevus variants, or Spitz nevi. Some authors have proposed the term “nevus with phenotypic heterogeneity ” for this group of melanocytic lesions. However, the terminology has not been widely accepted, possibly because the term “phenotypic heterogeneity ” may instigate clinical concern about the nature of the lesion. The most common combination is a compound nevus with congenital pattern along with a group of dendritic melanocytes in the center (blue nevus). This focus of blue nevus can be very small and composed only of few dendritic melanocytes and melanophages (in some occasions can be large and occupy most of the lesion).


Compound Blue Nevus


This is a rare variant of blue nevus defined by the presence of an intraepidermal component. It shows all the features of a common blue nevus but with an obvious junctional component. The lesions are symmetrical with slight epidermal hyperplasia and basal layer hyperpigmentation along with a junctional component of heavily pigmented dendritic melanocytes arranged as solitary units at the dermal epidermal junction. In rare occasions, these dendritic melanocytes can reach the upper layers of epidermis. Junctional nests are absent. The dermal component shows pigmented dendritic melanocytes arranged singly and in fascicles, similar to classic blue nevus [28, 36, 37]. In some cases, the dermal component can be heavily pigmented and so rich in melanophages that the cellular details of the melanocytes are barely distinguishable. Removal of pigment with special techniques such as potassium permanganate helps to identify the cellular component.


Amelanotic Blue Nevus


It may be considered either a variant of or be the same as desmoplastic nevus (see below). Clinically, this variant is usually either white or skin colored. Histologically, it shows a poorly defined, dermal proliferation of spindle cells associated with variable desmoplastic stroma (very similar to the classic variant) with thick collagen bundles in a scar-like pattern. In contrast to classic blue nevi, they are characterized by absent or minimal melanin pigment within the spindle melanocytic cells. When pigment is present, it is usually located at the edges of the lesion. The tumor cells have indistinct eosinophilic cytoplasm and fusiform hyperchromatic nuclei often containing small nucleoli. Intranuclear cytoplasmic pseudoinclusions are occasionally present, and mitotic figures are exceptional. The diagnosis can be challenging as lesions can mimic a scar, neurofibroma, dermatofibroma, or even desmoplastic melanoma. In difficult cases, immunohistochemistry can be of aid as the cells usually express HMB-45 antigen. S100 and MART-1 are also expressed.


Desmoplastic (Sclerosing) Blue Nevus


This variant of blue nevus is very important to be aware of as in some instances it may mimic a desmoplastic melanoma. Histologically, it shows features of classic blue nevi but associated with marked dermal fibrosis and sclerosis. Diagnostic clues include the presence of a symmetrical and inverted wedge-shaped configuration of the lesion and extension into deep dermis along adnexal structures and neurovascular bundles. The diagnosis can be established by the proper identification of dermal dendritic melanocytes; however, in some cases the lesions are quite paucicellular which makes difficult to identify them appropriately. The dendritic cells tend to be more abundant and easier to identify at the periphery of the lesion. As with other nevi, there may be neurotropism, but, in contrast with desmoplastic melanoma, there is no involvement of the endoneurium. This desmoplastic variant may indeed represent the later stages of some blue nevi. In some cases, immunohistochemistry is required to confirm the melanocytic cell population (S100p, MART-1, and HMB-45).

The differential diagnosis of this variant is primarily with desmoplastic melanoma . The distinction can be achieved in adequate excisional biopsies that permit evaluation of all the factors relevant for the diagnosis. However, both lesions will display spindled melanocytes and desmoplastic stroma. Diagnostic clues favoring desmoplastic melanoma include infiltrative, asymmetric silhouette, amelanotic appearance, obvious cytologic atypia (prominent nucleoli, hyperchromasia, and pleomorphism), and lymphoid aggregates. If the desmoplastic dermal melanocytic proliferation is accompanied by obvious melanoma in situ, the diagnosis is straightforward; however, in one third of desmoplastic melanomas, there is no in situ component detectable within the epidermis. Desmoplastic melanoma only rarely shows increased mitotic activity, but this is never seen in desmoplastic blue nevus. Intraneural invasion is present in desmoplastic melanoma and absent in sclerosing blue nevi. Ancillary immunohistochemistry studies have been used for problematic sclerosing melanocytic proliferations, such as the use of Ki-67, HMB-45, and MART-1. Desmoplastic melanoma tends to have a higher Ki-67 labeling index than melanocytic nevus, patchy HMB-45 labeling, and minimal expression of MART-1, while sclerosing blue nevi usually show a low cell proliferation index with Ki-67 and diffuse labeling with HMB-45 and anti-MART-1 [31, 38]. Also, it has been proposed that immunohistochemical staining for p16 may be helpful in such distinction, as the majority of desmoplastic melanomas lack p16 expression; however, in our experience desmoplastic melanoma commonly expresses p16 at least focally; thus it is not a valid marker for such distinction [39]. Occasional cases of desmoplastic melanoma may have a very low Ki-67 labeling index or may be immunoreactive for MART-1; thus, these markers should be used with caution. A recent study using a four-probe fluorescence in situ hybridization (FISH) assay targeting RREB1, MYB, Cep6, and CCND1 showed that 47 % of desmoplastic melanomas had detectable aberrations in the probe sites by FISH, while none of sclerosing melanocytic nevi (including sclerosing blue nevi) showed any level of chromosomal aberrations that met FISH criteria for melanoma [40]. This study concluded that a positive FISH test strongly supports the diagnosis of melanoma in this context; however, in this setting a negative FISH test was of limited diagnostic value.


Blue Nevus with Atypical Cells


In certain occasions common blue nevi can show cellular atypia . This cytologic atypia is usually focal and not extensive but can be striking as cells may show ample cytoplasm with large hyperchromatic nuclei and conspicuous nucleoli (similar to the cellular atypia noted in benign Spitz nevi). However, these lesions are small in size, symmetric, and wedge shaped and lack mitotic figures.

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Fig. 2.5
Combined blue nevus. The pigmented lesion is located in the arm of a 32-year-old male. This lesion is composed of two components; there is an intradermal nevus in the center of the lesion and on the sides the lesion clearly depicts a blue cell component (a). The center of the lesion shows the intradermal component. Note the balloon cell changes in some of the cells (b). Note the blue cell component clearly illustrated at the lateral side of the lesion (c)


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Fig. 2.6
Combined blue nevus. The lesion is located in the buttock of a 65-year-old male. The blue nevus component is located at the base of the lesion and above it is the intradermal component (a). The lesion displays aggregates of dendritic melanocytes at the base of the lesion. Note the absence of atypia and mitotic figures (b). Observe the aggregates of dendritic melanocytes in the dermis and focally around the erector pili muscle (c). Higher magnification showing marked hyperpigmentation (blue color clinically) (d)


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Fig. 2.7
Combined blue nevus. This image shows a polypoid lesion with a clear amelanotic blue cell component in the background and admixed with an intradermal nevus (a). The lesion depicts normal maturation toward the base and lack of cytologic atypia (b). The lesion shows dendritic melanocytes devoid of pigment (c)


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Fig. 2.8
Combined blue nevus. This lesion shows blue nevus admixed with many spitzoid melanocytes (a). The spitzoid component is composed of small- and medium-sized epithelioid melanocytes admixed with many scattered pigmented dendritic melanocytes (b). Note the normal maturation toward the base. The melanocytes lack cytologic atypia and devoid of mitotic figures (c). High power shows the spitzoid melanocytes interspersed between the collagen bundles (d)


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Fig. 2.9
Compound blue nevus. This example has an amelanotic blue component with an overlying junctional component (a). Note the basal layer hyperpigmentation along with single melanocytes in the epidermis (b). Normal maturation of melanocytes (c)


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Fig. 2.10
Amelanotic blue nevus. This case shows the dendritic spindle cells in superficial and reticular dermis. Note the scant pigment throughout the lesion (a). The center of the lesion is devoid of pigment with only minimal pigment observed in the deep component of the lesion (b). High power of the deep portion shows only rare pigmented dendritic cells (c)


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Fig. 2.11
Amelanotic blue nevus. The low-power magnification shows a papule composed of spindle melanocytes admixed with many dendritic cells (a). Note increased thickening of the collagen bundles and melanocytes interspersed in between them (b). Higher magnification shows banal appearance of the melanocytes along with lack of mitotic figures (c). Note the homogeneity of the spindle cell melanocytes (d)


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Fig. 2.12
Sclerotic blue nevus. Scalp of a 48-year-old female. The biopsy shows a pigmented nodular and symmetric lesion extending deep into the dermis. There is increased fibrosis and sclerosis. Note the bottom of the lesion shows bulbous aggregations (a). A different area of the same tumor showing a wedge-shaped nodular growth with marked fibrosis and sclerosis. There are heavily pigmented dendritic melanocytes arranged in small fascicles within a sclerotic stroma (b, c). A more paucicellular area and with more pronounced sclerosis and fibroplasia (d). Note the deep extension along adnexal structures (e). The propensity of the dendritic cells to wrap around the adnexal structures (f)


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Fig. 2.13
Sclerotic amelanotic blue nevus. The lesion shows a well-delineated nodule in reticular dermis composed of spindle dendritic cells and devoid of pigment (a). The spindle cells are arranged in small fascicles (b). The dendritic nature of the spindle cell melanocytes without pigmentation (c, d). In cases wherein there is doubt about the etiology of the spindle cells, MART-1 is a helpful marker to stain the cells


Epithelioid Blue Nevus (Pigmented Epithelioid Melanocytomas)



Clinical Features


Epithelioid blue nevus is a rare histologic variant of blue nevus that was first introduced in patients with Carney complex (myxomas, endocrine overactivity, spotty skin pigmentation, psammomatous melanotic schwannomas, thyroid neoplasms, etc.). Nonetheless, there are sporadic lesions that are histomorphologically indistinguishable from epithelioid blue nevi of Carney complex and have been referred to as pigmented epithelioid melanocytomas (PEMs) or animal-type melanoma (pigment synthesizing melanoma) . The current preferred term is PEM as it may reflect the intermediate malignant potential of this tumor.

These neoplasms have a predilection for children, adolescents, and young adults, but they occur over a broad age range. The most common location includes trunk and extremities; however, it can have a wide distribution, including mucosal sites, and thus suggesting that sun exposure is unlikely to be a major factor in its pathogenesis. The majority of tumors apparently arise de novo, but occasional lesions can be associated with a dermal nevus. These neoplasms are currently referred as low-grade melanocytic tumors since they may involve regional lymph nodes but have limited ability to spread beyond lymph nodes. Lymph node metastasis was detected in 46 % of cases in one series [22, 4143]. However, they have a favorable clinical outcome in most cases [43], and the prognosis is significantly more favorable than that of conventional melanoma. It is questionable whether epithelioid blue nevus patients would benefit from sentinel lymph node (SLN) biopsy as positivity does not seem to predict the outcome of the disease [4447].


Histopathology


Histologically, epithelioid blue nevus is composed of a poorly defined, heavily pigmented, dermal melanocytic proliferation with infiltrative or pushing borders, and not uncommonly these lesions may invade the subcutaneous fat. The dermal proliferation often but not always abuts the epidermis and in some examples may even show a grenz zone. The overlying epidermis in some occasions may show hyperplasia and elongated rete ridges. Some lesions may show a minor junctional component, as rare intraepidermal melanocytes are usually dendritic.

The lesions tend to be more cellular in the center, while in the periphery the tumor cells permeate between preexisting collagen fibers. The tumor is composed of a mixture of epithelioid and spindled, heavily pigmented melanocytes. The epithelioid cells range in size from medium to large and contain moderate to abundant amounts of coarsely granular, cytoplasmic melanin pigment and dispersed uniform nuclear chromatin and small distinct nucleoli. In some epithelioid cells, the pigment is dispersed evenly throughout the cytoplasm, but in other cells, the pigment is located at the periphery, leading to a pigment-free perinuclear zone. Nuclear atypia is generally more pronounced in the larger cells. The spindled cells are present singly or forming small groups and more commonly seen at the periphery of the lesion (checkerboard pattern). These spindle cells have the same nuclear features as those seen in the epithelioid cells; however, some of them show similar features to those observed in common blue nevus (pigmented cells with delicate dendrites). Melanocytes can infiltrate the adnexal epithelium, pilar erector muscles, perivascular spaces, and perineurium. The neoplastic cells lack maturation with depth and mitotic activity is occasionally seen (mostly ranging from 0 to 2 mitotic figures/mm2), without atypical forms. Tumor necrosis is rarely seen [23].

Also, there have been reported cases of epithelioid blue nevi occurring in chronically sun-damaged skin with a predominance of epithelioid morphology but also containing a component of fusiform and conventional blue nevus cells, which has been termed “epithelioid and fusiform blue nevus of chronically sun-damaged skin” [48]. These lesions are more commonly seen in older patients, obviously with a predilection for sun-exposed areas. Distinguishing histopathologic features of epithelioid and fusiform blue nevus of chronically sun-damaged skin from PEMs include the presence of solar elastotic bundles and a higher frequency of an associated conventional blue nevus component. A small subset of cases has marked pleomorphism and nuclear atypia with rare mitotic activity and with the accompanying solar elastosis, thus raising concern for the possibility of melanoma.


Differential Diagnosis


The epithelioid blue nevus seen in Carney syndrome is histologically identical to the sporadic counterpart. The differential diagnosis of epithelioid blue nevus is primarily with deep penetrating nevus (DPN) . DPN causes significant histologic confusion due to its resemblance to epithelioid blue nevus, as they are deeply pigmented dermal tumors with wedge-shaped architecture, show subcutaneous fat involvement, and both have pigmented spindle cells with common periadnexal or perivascular extension. Furthermore, several authors, among them are one of us, consider DPN a variant of cellular blue nevi. In the classical description, in DPN the melanocytes are arranged in a plexiform pattern with large nests and fascicles and are not as uniformly pigmented as in epithelioid blue nevus. Also, in DPN the cells have smudged nuclear chromatin (open vesicular nuclei in epithelioid blue nevus) and variable nuclear atypia and pleomorphism with prominent intranuclear inclusions. Also, the presence of prominent nucleoli is a characteristic finding in epithelioid blue nevus. DPNs are benign melanocytic neoplasms and only rarely recur.

Epithelioid blue nevus can have similar architectural features to cellular blue nevi, including periadnexal and subcutaneous extensions and a dumbbell architecture on low-power magnification. In our opinion, one of the most specific differentiating features between epithelioid blue nevus and cellular blue nevi is the presence of epithelioid cells in the former, which are absent in cellular blue nevi. Dermal sclerosis, common in blue nevi, is only rarely observed in epithelioid blue nevus. Also, epithelioid blue nevus tends to have infiltrating borders while cellular blue nevi do not, as the cellular nodules tend to be well circumscribed. The differential diagnosis between epithelioid blue nevus and blue nevus-like melanoma (BNLM) may be challenging because of the at least focal presence of severely atypical epithelioid cells in both neoplasms. The most important differentiating features are the presence of cellular blue nevus component, monotonous high-grade cytological atypia, high mitotic activity (atypical mitotic figures), and tumor necrosis in BNLM.


Immunohistochemistry and Molecular Testing


A recent study analyzed mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene, loss of heterozygosity (LOH) at the gene locus 17q22-24, and expression of PRKAR1A by immunohistochemistry in PEMs, in a variety of nevi and in melanomas [49]. This study showed that there are no PRKAR1A gene mutations, a protein that is mutated in 50 % of patients with Carney complex [49], in PEMs, in nevi, or in melanomas; however, most PEMs (up to 82 %) and Carney complex-associated epithelioid blue nevi lose expression of PRKAR1A by immunohistochemistry. Also, five of the seven PEMs studied in that series showed 17q22-24 LOH. PRKAR1A protein is expressed in virtually all melanomas and some melanocytic nevi [49]; thus, loss of expression of PRKAR1A may offer a useful diagnostic test that helps to distinguish PEM from its histologic mimics including conventional, cellular and malignant blue nevi, and deep penetrating nevi. Also, these findings provide a molecular basis supporting the common phenotype of Carney complex-associated and sporadic cases of PEMs. Additionally, a recent study showed the presence of GNAQ mutations (20 % of cases) and the absence of HRAS and GNA11 mutations in PEMs; thus, these studies provided molecular support for the classification of these tumors as variants of blue nevi [50]. In contrast, the “epithelioid and fusiform blue nevus of chronically sun-damaged skin” seems to represent a unique subtype of blue nevus without association with Carney complex or loss of PRKAR1A expression (by IHC) typically found in PEMs and Carney complex-associated epithelioid blue nevi [48].

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Fig. 2.14
Pigmented epithelioid melanocytoma (PEM). This lesion is composed of heavily pigmented dermal melanocytes with infiltrative borders (a). The cells are mostly epithelioid and with abundant heavily pigmented cytoplasm and forming cohesive sheets of closely packed uniform cells (b)


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Fig. 2.15
Pigmented epithelioid melanocytoma (PEM). This example shows a heavily pigmented dermal lesion with an inverted wedge-shaped architecture abutting the epidermis and inducing mild epidermal hyperplasia (a). This tumor is composed of variably pigmented epithelioid and spindle cells with prominent nucleoli, interspersed with many melanophages (b). Rare mitotic figures can be present (usually <2 mitoses per mm2) (c). Note the dot-like melanin granules at the periphery of the cell (d)


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Fig. 2.16
Pigmented epithelioid melanocytoma (PEM). Another example of PEM showing a heavily pigmented dermal melanocytic tumor with infiltrative borders. The figure below represents a bleached slide to visualize better the tumor cytology


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Fig. 2.17
Pigmented epithelioid melanocytoma (PEM). Scanning magnification shows a heavily pigmented dermal melanocytic tumor extending into the subcutaneous tissue along eccrine coils (a). The epithelioid cells are intermixed with a variable number of spindled cells. The spindle cells penetrate between the surrounding stromal collagen bundles (b). The spindle and epithelioid cells are infiltrating along the eccrine ducts in the deep dermis (c). The melanocytes have a heavily pigmented cytoplasm forming cohesive sheets of closely packed uniform cells (d)


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Fig. 2.18
Pigmented epithelioid melanocytoma (PEM) of the vulva. The lesion is composed of discrete aggregates of epithelioid heavily pigmented melanocytes (a). Some authors may consider this lesion as epithelioid blue nevus. These lesions are common on genital areas and show aggregates of epithelioid pigmented melanocytes (bd)


Cellular Blue Nevus



Clinical Features


Cellular blue nevi (CBN) are dermal melanocytic neoplasms that are present at all ages, but are most commonly seen in young adults with slight female predominance. Rarely, they may have a congenital onset. The most common sites of involvement include the buttocks/sacrococcygeal region and the scalp, also the face, extremities, genital tract, breast, subungual region, intraocular, and conjunctiva. It presents as a large, pigmented, multinodular mass that ranges in size from few millimeters to up to 6 cm (most lesions measure between 1 and 3 cm) [22, 23, 51, 52].

CBN may involve the subcapsular sinuses and even the parenchyma of regional lymph nodes, but the latter is an exceedingly rare phenomenon [5355]. Such deposits of CBN in lymph nodes may pose difficulties when trying to distinguish CBN from BNLM [53]. Comparison with the histology of the primary cutaneous tumor may help to arrive at the correct diagnosis and prevent inappropriate treatment. This phenomenon does not appear to represent true metastases as it seems not to alter the prognosis of CBNs. The few previous reports of patients affected by CBN with lymph node metastases reported survival without recurrence of the disease for 5, 10, and 22 years after conservative surgery [55]. The risk for malignant transformation and developing melanoma in cellular blue nevi has been estimated to be between 5.2 and 6.3 % [56, 57].


Histopathology


Histologically, most lesions appear well defined and extend deeper into the dermis and/or subcutis in a typical dumbbell pattern. At low magnification the tumor shows pigmented alternating zones of hypercellularity with collagenous hypocellular pigmented foci. It may present as a pigmented biphasic tumor with a component of a common blue nevus and distinct cellular areas comprised of larger, plump oval to fusiform spindle cells with small monomorphous nuclei with speckled chromatin, small nucleoli, and more abundant, clear, or finely pigmented cytoplasm. In the more superficial and peripheral aspects of the lesion, the appearance is often of a classic blue nevus with varying amounts of stromal fibrosis and desmoplasia, and in the center and deeper portions, the cellularity is increased. The cellular areas are arranged in short fascicles or nests, in solid sheets, or in a plexiform pattern. Around the periphery of the nested pattern, there is a wreath of dendritic pigmented melanocytes admixed with pigmented melanophages. Most of the pigment observed is in the macrophages (i.e., melanophages) and the pigmented dendritic cells, whereas the melanocytes are usually only lightly pigmented or amelanotic. In many cases an alveolar growth pattern is seen, which is predominantly characterized by a small, well-defined, nested arrangement of epithelioid, amelanotic melanocytes surrounded by dense collagen, pigmented dendritic melanocytes, and melanophages. Also, there are commonly elongated slender melanocytes resembling Schwann cells in a neurotized pattern (similar to ordinary nevi). Mitotic figures should be absent or only focal; up two per ten high-power fields may be considered the upper limit in CBNs.

The stroma in these lesions is sclerotic. Sometimes there are multinucleated wreath-like giant cells and balloon cells, but nuclear pleomorphism is rare. A characteristic feature of cellular blue nevi is the presence of central, cystic degeneration. Myxoid degeneration, hemorrhage, and stromal hyalinization can also occur. Nerve hypertrophy is often present with perineural aggregation of cells. Not unusually cellular blue nevi may display balloon melanocytes [58]. Kazakov et al. [59] reported the presence of “ball in mitts” structures in cellular blue nevi, which are composed of a single centrally placed rounded melanocyte (ball) encircled by a single dendritic cell (mitt). They also reported “microalveolar structures,” composed of two to ten central rounded cells surrounded by one or more dendritic cells similar to those seen in the “ball in mitts” structures. The same authors noted that similar structures may occur in combined nevi, deep penetrating nevi, acquired melanocytic nevi, and classic blue nevi.

Cellular blue nevi may show unusual features such as the presence of rare mitotic figures, focal nuclear pleomorphism, and focal necrosis, but not all three features simultaneously. These cases have been named atypical cellular blue nevi (see below) [60, 61]. When seen, mitotic figures can even be present in the deeper aspect of the tumor; however, atypical forms are not observed. We report the presence of isolated mitotic activity or focal necrosis in the absence of other atypical findings (such as nuclear atypia or expansile growth pattern) is indicative of atypical cellular blue nevus although the possibility of aggressive behavior appears to be low [61, 62].

Different thresholds exist as to what is the amount of cellular areas allowed within a common blue nevus. We use the term CBN in lesions with cellular areas noticeably present and particularly if the lesion is large enough (>1 cm). Cellular blue nevi have a greater potential for recurrence and local aggressive growth than do common blue nevi; thus, correct identification is advised. Furthermore, the risk of malignant transformation is significantly higher for the cellular blue than common blue nevus, although still quite rare. Ideally, all cellular blue nevi should be completely excised.


Differential Diagnosis


The main differential diagnosis of cellular blue nevi is with blue nevus-like melanoma (BNLM) . Like BNLM, CBN is usually composed of large epithelioid and/or spindle cells, lacks maturation with depth, may extend deeply, may be pigmented, and may contain occasional mitotic figures. The distinction will be made based on the proper identification of severe cytologic atypia, obvious tumor necrosis, high mitotic count (>2/mm2), atypical mitotic figures, large expansile nodules, and diffuse infiltrative borders; all these will favor the diagnosis of BNLM. Other histologic findings that favor BNLM over CBN include the presence of large pleomorphic epithelioid cells, cell crowding, an “infiltrating” growth pattern (margins of the tumor are irregular, as opposed to the pushing margins of CBN), and expansile growth. The cells in CBN have bland nuclear qualities in most cells as opposed to BNLM which show marked variability of nuclear chromasia, size, and shape. Also, the architectural disposition of the biphasic elements seen in CBN is not observed in BNLM; in contrast, there is effacement of the dermal architecture by a densely cellular proliferation. Neurotropism can be observed in both cellular blue nevi and BNLM. BNLM may show multiple chromosomal aberrations with FISH or CGH analysis.

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Sep 27, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Dermal Melanocytoses
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