Blue Nevi and Dermal Melanocytosis

Mongolian Spot.

Mongolian spots are gray-blue to brown macules or patches located in the lumbosacral/gluteal region. They affect a majority of Asians, African Americans, and American Indians but are rare in Caucasians. The lesions are present at birth but often spontaneously regress within a few years. However, some lesions may persist until the second decade or even into adulthood. To our knowledge, melanoma has not been reported yet to have evolved in a Mongolian spot.

Nevus of Ota (a.k.a. “Oculo-Dermal Melanocytosis” or “Nevus Fuscoceruleus Ophthalmomaxillaris”).

Large lightly bluish or brownish discoloration affects the area of skin innerved by the second and the third branch of the trigeminal nerve (see Fig. 5.1 ). The condition usually presents at birth or in childhood, but delayed onset in adolescence is also known to occur. It is most often seen in Asians, in approximately 1 out of 1000 individuals, but can also be found in Caucasians. There is a predilection for women. The discoloration is usually unilateral, but bilateral presentations have been reported. Affected areas include the periorbital region, forehead, temple, cheek, or nose. The process may involve a relatively small region, but usually extends beyond the skin and may also involve the conjunctiva, cornea, sclera, retina, periorbital soft tissue, meninges, and/or the oral and nasal mucosa and submucosa. Sometimes the involved area may be limited to the conjunctiva and soft tissue without apparent cutaneous manifestations. In contrast to Mongolian spots, nevus of Ota usually does not fade away. It persists throughout life and may enlarge and/or darken.

Cutaneous melanoma may arise in the setting of a nevus of Ota, but this is a rare scenario. Approximately 50 such cases have been reported—most in Caucasians, typically middle-aged to elderly. The majority of melanomas developing in association with nevus of Ota are choroidal melanomas. The risk for developing choroidal melanoma is approximately 20 times greater in Caucasians with nevus of Ota compared with the general population. In other ethnic groups, nevus of Ota does not seem to confer a significant increase in risk for choroidal melanoma.

Nevus of Ota has been associated with other melanocytoses (e.g., nevus of Ito, leptomeningeal melanocytosis) and vascular and central nervous system anomalies (e.g., Sturge-Weber syndrome, Klippel-Trenaunay syndrome, nevus flammeus).

Nevus of Ito (a.k.a. “Nevus Fuscoceruleus Acromiodeltoideus”).

Nevus of Ito is a unilateral usually congenital mottled brown and bluish discoloration of the cutaneous territory of the posterior subclavian and branchial-cutaneous nerves. Like nevus of Ota, it tends to persist and does not fade away with time. A rare case of melanoma arising in nevus of Ito has been reported.

Nevus of Sun (Nevus Fusco-Caeruleus Zygomaticus) and Nevus of Hori (Acquired Bilateral Nevus of Ota-Like Macules).

Sun reported in 1987 a lesion in Asians similar to nevus of Ota but different from it in several aspects. It involved the area of the zygomatic (not ophthalmic) branch of the trigeminal nerve, tended to be smaller in size, spared the eye structures or sinonasal mucosa, its bluish discoloration was usually speckled (not homogenous), and the lesion was acquired (not congenital). A bilateral presentation of nevus of Sun has been referred to as nevus of Hori. No melanoma has yet been reported to arise in nevus of Sun or Hori.

Acquired Dermal Melanocytosis of the Face and Extremities.

This group of lesions resembles nevus of Ota, but with onset in adults and a different anatomic distribution, involving various parts of the face and/or extremities. It is not associated with a known syndrome and does not regress. So far no melanoma has been reported to arise in it.

Dermal Melanocyte Hamartoma.

The term dermal melanocyte hamartoma refers to a group of dermal melanocytoses covering large areas of the skin, which are typically present at birth, and occasionally associated with a congenital anomaly.

Clinical Findings and Variants of Common Blue Nevus.

The common BN is a well-demarcated, slightly raised, or dome-shaped bluish or bluish-black papule, usually measuring less than 1 cm in diameter ( Fig. 5.3 ). Preferred anatomic locations include the dorsal aspects of the hands and feet, the face, and the scalp ( Box 5.1 ). Lesions generally become clinically manifest in adolescents or young adults but may occur at any age—from early childhood to very late in life. Most common BN are solitary.

Some individuals have multiple lesions. Agminated forms had also been reported as well as multiple lesions throughout the body. It is extremely rare that melanoma develops in association with a common blue nevus. Multiple BN may occur in the sporadic setting or associated with the Carney complex or other familial conditions. A discrete set of multiple small BN may be arranged in a linear fashion (linear BN).

Individual lesions of a BN may have a unique appearance; they may be targetoid, patch, or plaque-like. BN may also be distinguished by the mode of onset (congenital vs. acquired), nevus context (BN within a congenital nevus or nevus of spilus), or anatomic site (BN of special site, such as subungual nevus).

Histopathologic Findings.

There is an aggregation of usually pigmented melanocytes, generally in the upper reticular dermis ( Fig. 5.4 ). The lesion melanocytes characteristically display slender elongated fusiform and dendritic processes and contain fine melanin granules. The nuclei are slightly elongated ovoids with uniform delicate chromatin pattern. Junctional melanocyte nests are absent. Most intradermal melanocytes are typically dispersed as individual units, but the cell density is significantly higher than in a dermal melanocytosis. Dense cell aggregates or compact fascicles of cells may occur in larger lesions, but are generally rare and constitute only a minor component. Most lesions are small and removed by a shave biopsy; some lesions are larger, involving much of the reticular dermis or even subcutis ( Fig. 5.5 ). Lesional melanocytes are often oriented parallel to the epidermis, except when they are dispersed in the stroma around skin appendages and neurovascular bundles. In some lesions, the association with hair follicles is prominent ( Fig. 5.6 ). The common blue nevus often shows variable degrees of fibrosis ( Fig. 5.7 ). Some stromal fibrosis is often present, but it may be absent. In contrast to most other nevi, BN lack zonation (“maturation”; i.e., the phenotype of slender and fusiform melanocytes is usually the same from the top to bottom of the lesion). Perineural and/or periadnexal attributes (melanocytes wrapping around nerve twigs and/or adnexal structures) are commonly seen. Mitotic figures are usually absent. Inflammation is rare, but on occasion patchy lymphocytic aggregates may be present.

In BN, there are often melanophages and fibroblasts admixed. Melanophages vary in number and proportion: they may be sparse or dominant. Melanophages differ from melanocytes by the lack of dendritic processes, their polygonal morphology, and the presence of coarser melanin granules. Fibroblasts are more prominent in lesions associated with stromal fibrosis.

Immunohistochemically, the lesional cells of BN are usually positive for melanocyte differentiation antigens, especially melan-A/Mart1 and gp100 (HMB-45). The melanocytes of BN may on occasion stain only weakly for S100 protein. Lesional melanocytes are best distinguished from melanophages by nuclear labeling for Sox10, or after bleaching using an immunostain for HMB-45 with a red chromogen.

Blue Nevus Versus Melanocytosis.

The common BN differs from melanocytosis by a greater concentration of melanocytes. In contrast to melanocytosis, the BN is accompanied by varying degrees of fibrosis and melanophage accumulation.

Blue Nevus Versus Melanosis.

Focal collections of pigmented dermal dendritic cells and melanophages may occur in the setting of postinflammatory hyperpigmentation, and possibly lead to an erroneous diagnosis of BN. Pigmented inflammatory dendritic cells are best distinguished from dendritic melanocytes by a combination of histopathologic features (e.g., fine dusty melanin pigment within melanocytes) and immunohistochemical studies using nuclear markers (Sox10) or red chromogens for melanocyte differentiation antigens. Caution is needed for interpretation of cytoplasmic markers, since melanin pigment in macrophages may lead to false-positive labeling.

Blue Nevus Versus Combined Nevus.

A typical BN lacks an associated intraepidermal melanocyte proliferation with junctional nests. The presence of the latter, especially in the context of an additional cell population of conventional or other nevus, represents a combined nevus. BN is typically associated with a nevus with a superficial congenital pattern or ordinary acquired nevus, but may be a part of any type of nevus.

Blue Nevus Versus Blue Nevi-Like Melanoma.

A common BN is usually readily recognized by its three morphologic elements (dendritic melanocytes, melanophages, fibrosis) and nearly always easily distinguished from melanoma. It is extremely rare for a primary melanoma to simulate the clinical or histopathologic appearance of a common BN. Blue nevus–like melanoma is morphologically recognized by the presence of atypical epithelioid cells, mitoses, and/or an unusual proportion of melanophages.

A distinct challenge is the distinction of BN of sun-damaged skin from desmoplastic melanoma (DM). The term epithelioid and fusiform blue nevus of chronically sun-damaged skin refers to this diagnostic problem. Typically BN of sun-damaged skin is a small and superficial lesion. Immunostains (strong labeling for melan-A), bland cytology, and the presence of typical slender fusiform pigmented melanocytes help distinguish a BN of sun-damaged skin from DM. Another challenging scenario can be distinction of BN and BN-like melanoma in a subungual location with only a partial biopsy for review. In problematic cases, ancillary studies can help establish a diagnosis: the presence of cytogenetic aberrations favors melanoma.

Blue Nevus Versus Metastatic Blue Nevi-Like Melanoma.

An important differential diagnosis is the distinction of a BN from metastatic melanoma, which on occasion may simulate the clinical and histopathologic appearance of a common BN. BN can be distinguished from BN-like metastatic melanoma by clinical context and cytologic and, if necessary, cytogenetic features. A prior history of cutaneous, mucosal, or ocular melanoma and the sudden appearance of a bluish macule or papule, especially in an anatomic region near the primary site, should prompt concerns about a possible cutaneous metastasis. Histopathologic clues to the diagnosis of metastatic melanoma include the presence of atypical epithelioid cells and mitotic figures. However, at times the distinction of BN from BN-like metastatic melanoma can be difficult, especially when the clinical history and presentation are unknown or unclear. If unusual histopathologic findings are noted (a few mitotic figures), cytogenetic analysis and/or immunohistochemistry can be very helpful. Metastatic cutaneous or ocular melanoma commonly harbor chromosomal copy number changes, which are not expected to occur in ordinary common BN. Monosomy 3, for example, is a common feature of metastatic ocular melanoma, and would not be expected to be found in an ordinary BN. Metastatic ocular melanomas commonly show loss of nuclear labeling for BAP1. A common BN should uniformly express BAP1.