Benign Melanocytic Tumors

1

What is a mole?

A mole is a small burrowing mammal belonging to the family Talpidae. It is also a term commonly used to describe a melanocytic nevus.

2

What is a nevus?

Derived from the Latin term meaning “spot” or “blemish,” nevus was originally used to describe a congenital lesion or birthmark (mother's mark). In modern usage, the term describes cutaneous hamartoma, or benign proliferation of cells. However, when the term is used without a descriptive adjective, it usually refers to a melanocytic nevus. Examples of nevi used in the context of a birthmark are epidermal nevus and nevus sebaceus.

3

Are there different types of melanocytic nevi?

Yes. Melanocytic nevi can be classified according to their histology based on (1) location of the nevus cells (e.g., junctional, compound, or intradermal nevi), (2) cytologic atypia (e.g., atypical [dysplastic] nevi), and (3) morphology and architectural arrangement of nevus cells (e.g., Spitz and spindle cell nevi). Melanocytic nevi can also be classified based on their appearance (e.g., halo nevi or blue nevi). In addition, there are congenital melanocytic and acquired nevi.

4

How do melanocytes get to the skin?

Melanocytes arise from the cranial and truncal neural crest cells in embryonic life. The development of melanocytes from neural crest cells, as well as their ability to migrate, is dependent upon interactions between specific receptors and extracellular ligands, including endothelin 3 and the endothelin B receptors, α-melanocyte-stimulating hormone and the melanocortin-1 receptor, stem cell factor (SCF), and its receptor KIT, each of which induces the expression of microphthalmia-associated transcription factor (MITF). MITF is the most critical regulator of pigment cell development and survival. Bone morphogenic protein is a negative regulator of this process.

Melanocytes migrate via the mesenchyme and reach their final location in the skin, uveal tract of the eye (choroid, ciliary body, and iris), leptomeninges, inner ear (cochlea), and sympathetic chain lining the colon early during embryogenesis. The melanocytes that migrate to the skin take up residence on the epidermal side of the dermal–epidermal junction and the basal layer of the hair matrix, as well as the outer root sheath of the bulge region of the hair follicle. The latter region is where melanocyte stem cells are thought to reside.

5

Explain the natural developmental history of melanocytic nevi

Melanocytic nevus cells are derived from melanocytes and differ from normal epidermal melanocytes in a number of ways. They are no longer dendritic, they do not distribute melanin to surrounding keratinocytes, and they are less metabolically active. The development of melanocytic nevi is multifactorial, and the molecular events underlying the development of nevi are still being investigated. Much of the available information related to the genetics of benign nevi is restricted to the analysis of genes related to melanomagenesis. Melanocytic nevi are benign clonal proliferations of cells expressing the melanocytic phenotype and are thought to be derived from precursor cells that acquire genetic mutations. These mutations activate proliferative pathways and/or suppress apoptosis, allowing for the accumulation of melanocytic cells in the skin. It is believed that at some point after proliferation, a senescence program is activated, causing termination of nevi growth. Malignant transformation of a nevus is thought to be due to the emergence of additional tumorigenic mutations, which provide an escape from oncogene-induced senescence.

The type of nevus that is formed is thought to be dependent upon specific gene mutations as well as local environmental factors. BRAF gene mutations are commonly seen in acquired melanocytic nevi. Acquired melanocytic nevi are thought to begin as a proliferation of nevus cells along the dermal–epidermal junction (forming a junctional nevus; Fig. 40.1 A ). With continued proliferation of nevus cells, they extend from the dermal–epidermal junction into the dermis (forming a compound nevus). The junctional component of the melanocytic nevus may resolve, leaving only an intradermal component (intradermal nevus; Fig. 40.1 B). However, it should be stressed that there is debate regarding the direction of nevus growth. Congenital melanocytic nevi and blue nevi frequently harbor NRAS and GNAQ mutations, respectively, while Spitz and atypical Spits tumors usually exhibit HRAS , BAP1 , and other kinase gene mutations.

Melanocytic nevi form naturally, possibly due to ultraviolet light exposure, from the ages of 6 months to 40 years and later. They may also resolve spontaneously. However, the appearance or disappearance of any melanocytic lesion should be brought to the attention of a physician.

Cane JF, Trainor PA. Neural crest stem and progenitor cells. Annu Rev Cell Dev Biol. 2006;22:267–286.

Grichnik JM, Ross AL, Schneider SL, et al. How, and from which sources, do nevi really develop? Exp Dermatol. 2014;23:310–313.

Roh MR, Eliades P, Gupta S, Tsao H. Genetics of melanocytic nevi. Pigment cell. Melanoma Res. 2015;28:661–672.

Dimonitsas E, Liakea A, Sakellariou S, et al. An update on molecular alterations in melanocytic tumors with emphasis on Spitzoid lesions. Ann Transl Med. 2018;6:249.

6

What is a halo nevus?

A halo nevus, also known as a Sutton's nevus or leukoderma acquisitum centrifugum, is an acquired or congenital melanocytic nevus (CMN) with a surrounding well-circumscribed annulus of hypo- or depigmented skin ( Fig. 40.1 C). Halo nevi can be solitary or multiple and generally affect individuals under the age of 20 years. In general, those patients with halo nevi have an overall increased number of melanocytic nevi. Halo nevi are commonly associated with vitiligo, with 20% to 50% of vitiligo patients demonstrating halo nevi. Conversely, less than 15% to 25% of patients with halo nevi have vitiligo. Although both halo nevi and vitiligo may look similar clinically, recent studies strongly suggest that halo nevi and vitiligo have separate pathogenetic mechanisms. Nevertheless, halo nevi are strong predictors of a subset of vitiligo patients and may be an initiating factor in the pathogenesis of vitiligo. Although not completely understood, the pathogenesis of halo nevi is thought to be related to (1) an immune response against antigenically altered nevus cells or (2) a cell-mediated or humoral immune response against nonspecifically altered nevus cells. It is not completely understood whether this represents an abnormal immunologic response or whether the immune system is recognizing an atypical clone of nevomelanocytes.

Although most pigmented lesions with halos are benign, malignant melanoma can rarely be seen with an associated halo. If a pigmented lesion has an irregular border and halo or shows other atypical features, it should be biopsied.

van Geel N, Vandenhaute S, Speeckaert R, et al. Prognostic value and clinical significance of halo naevi regarding vitiligo. Br J Dermatol. 2011;164:743–749.

van Geel N, Mollet I, Brochez L, et al. New insights in segmental vitiligo: case report and review of theories. Br J Dermatol. 2014; 166:240–246.

7

What is a congenital nevus?

A CMN is a nevus that is present at birth. For the purpose of management, any melanocytic nevus that arises during the first year of life is considered “congenital.” CMN are thought to arise between the 5th and 24th weeks of gestation due to morphologic error occurring in the neuroectoderm during embryogenesis, leading to unregulated growth of melanoblasts. The protooncogene CKIT that encodes the receptor allowing the binding of the SCF is believed to play an important role in the development of congenital nevi. CMN are permanent and grow in proportion to the child, covering the same anatomical area of skin as is affected at birth. CMN are usually characterized as small, large, or giant, although there is no universally accepted definition of these categories. Small CMN are usually defined as being up to 1.5 cm in diameter, large CMN as being between 1.5 and 20 cm in diameter, and giant CMN as being more than 20 cm in diameter. Another scheme for classifying small, large, and giant CMN considers the percentage of the body surface area the lesion covers, or the ease of surgical removal and repair of the resulting surgical defect. Still another classification scheme describes giant CMN as being as large as two of the patient's palms for lesions on the trunk and extremities, or the size of one palm for lesions on the face or neck ( Fig. 40.1 D). The estimated prevalence of CMN varies from 0.5% to 32%, with the majority of these lesions less than 3 to 4 cm in diameter. Large CMN are much less common and have an estimated incidence of 1 in 20,000 to 500,000 live births.

Turkmen A, Isik D, Bekerecioglu M. Comparison of classification systems for congenital melanocytic nevi. Dermatol Surg. 2010; 36:1554–1562.

Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis. J Am Acad Dermatol . 2012;67:e1–e17.

Viana AC, Gontijo B, Bittencourt FV. Giant congenital melanocytic nevus. An Bras Dermatol. 2013;88:863–878.

Vourc'h-Jourdain M, Martin L, Barbarot S. Large congenital melanocytic nevi: therapeutic management and melanoma risk: a systematic review. J Am Acad Dermatol. 2013;68:493–498.

8

What is the histology of a CMN?

There no absolutely specific histologic findings in CMN. Studies have shown there may be differences in histology depending on the age of the patient at the time of the biopsy. Findings that support the diagnosis of a CMN include the presence of deep nevus cells, particularly within adnexal structures, vessel walls, eccrine glands, and/or perineurium.

Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis. J Am Acad Dermatol . 2012;67:e1–e17.

9

What are the genetics of CMN?

Genes that have been described as mutated in a single CMN include NRAS, BRAF, MC1R, TP53 , and GNAQ . In patients with multiple CMN, postzygotic mutations in NRAS have been identified in 80% of CMN cases studied as well as in affected neurological and malignant tissue. In one large cohort, about one-third of CMN have been associated with a family history of CMN of any size and number in a first- or second-degree relative. In these cases, a significant increase in compound heterozygous or homozygous melanocortin-1 receptor (MC1R) variants has been identified and certain MC1R variants were associated with a more severe cutaneous phenotype of CMN. At present, the mechanism underlying MC1R variants and CMN phenotypes is not understood; however, this pattern mirrors that of sporadic adult melanoma. Whether patients with CMN with germline MC1R variants are at an increased risk of melanoma development is not yet known.

Kinsler VA, O'Hare P, Bulstrode N, et al. Melanoma in congenital melanocytic naevi. Br J Dermatol . 2017;176:1131–1143.

10

What is the risk of developing a malignant melanoma in a congenital nevus?

Although there is little agreement about the risk of developing melanoma within a CMN, some general guidelines can be stated. The risk appears to relate to the size of the CMN. A small or medium CMN does not appear to have any significantly greater risk for melanoma than an acquired melanocytic nevus, on the order of 1%–2%. However, this incidence varies with the severity of the congenital phenotype and size of the CMN. In this regard, while the risk for small single CMN is low, a large CMN > 40 cm projected adult size, accompanied by multiple smaller CMN, is associated with a lifetime melanoma risk of has 10 to 15%. This risk of melanoma in a CMN also appears to be higher in those patients with congenital abnormalities of the CNS. It is noteworthy that in about one-third of patients with CMN who develop melanoma, the primary melanoma develops within the central nervous system. While there is evidence that melanomas tend to arise earlier in life in giant CMN, the need for removal of congenital nevi is one of the most controversial issues in pediatric dermatology. It should be stressed that surgical removal of the CMN does not decrease a patient's risk for melanoma.

Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for Congenital Melanocytic Naevi: prospective study 1988–2007. Part 1—epidemiology, phenotype, and outcomes. Br J Dermatol. 2009;160:143–150.

Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for Congenital Melanocytic Naevi: prospective study 1988–2007. Part 2—evaluation of treatments. Br J Dermatol. 2009;160:387–392.

Vourc'h-Jourdain M, Martin L, Barbarot S. Large congenital melanocytic nevi: therapeutic management and melanoma risk: a systematic review. J Am Acad Dermatol. 2013;68:493–498.

Kinsler VA, O'Hare P, Bulstrode N, et al. Melanoma in congenital melanocytic naevi. Br J Dermatol . 2017;176:1131–1143.

11

What is a blue nevus?

Blue nevi and related melanocytic proliferations (i.e., congenital dermal melanocytoses including Mongolian spot, nevus of Ito, and nevus of Ota) are a heterogeneous group of congenital and acquired melanocytic lesions that have in common several clinical, histologic, and immunochemical features. They have been termed dermal dendritic melanocytic proliferations because they are usually composed, at least in part, of dendritic melanocytes within the dermis. The deep dermal location of the pigment-producing cells, and therefore the pigment, causes the lesion to have its blue, black, or gray appearance due to the Tyndall effect ( Fig. 40.2 ).

Blue nevi are usually acquired and have their onset most commonly in childhood and adolescence, but less than 25% are congenital. In general, melanocytes disappear from the dermis during embryonic migration, but some cells do remain in the scalp, sacral region, and dorsal aspect of the distal extremities. These sites correlate to the most common locations for blue nevi to occur. The three commonly identified varieties of blue nevi are the common blue nevus, cellular blue nevus, and combined blue nevus–melanocytic nevus. The vast majority of blue nevi harbor a somatic mutation in the G protein α-subunits of either GNAQ or GNA11 .