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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 a 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 sebaceous.

3. Are there different types of melanocytic nevi? Yes. Melanocytic nevi can be classifi ed 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 classifi ed 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 specifi c receptors and extracellular ligands, including endothelin 3 and the endothelin B receptors, �–melanocyte stimulating hormone and the melanocortin-1 receptor stem cell factor and its receptor KIT, each of which induce expression of the microphthalmia-associated transcription factor (MITF). MITF is the most critical regulator of pigment cell development and survival. Bone morphogenic protein (BMP) is a negative regulator of this process.

Melanocytes migrate via the mesenchyme and reach their fi nal 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, 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. 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 are thought to activate proliferative pathways and/or or suppress apoptosis, allowing for the accumulation of melanocytic cells in the skin. The type of nevus that is formed is thought to be dependent upon the specifi c mutation, as well as local environmental factors. B-Raf 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. 41-1 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. 41-1 B). However, it should be stressed that there is debate regarding the direction of nevus growth.

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 22:267–286, 2006. Grichnik J: Melanoma, nevogenesis, and stem cell biology, J Invest Dermatol 128:2365–2380, 2008.

6. What is a halo nevus? A halo nevus, also known as a Sutton’s nevus or leukoderma acquisitum centrifugum, is a melanocytic nevus with a surrounding well-circumscribed annulus of hypo- or depigmented skin ( Fig. 41-1 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

CHAP

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41 BENIGN MELANOCYTIC TUMORS Michael R. Campoli, MD, PhD, and Patrick Walsh, MD

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A

D

B

C

Figure 41-1. A, Junctional nevi are typically small, fl at, and dark brown in color. B, An intradermal nevus also may be very exophytic or papillomatous, as shown here. C, Typical halo nevus of the back demonstrating a central brownish-red papule. D , Large congenital nevus with multiple smaller congenital nevi. These lesions present a surgical challenge and a signifi cant cosmetic problem.

overall increased number of melanocytic nevi. Halo nevi are commonly associated with vitiligo, with �20% to 50% of vitiligo patients demonstrating halo nevi. Conversely, �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. 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 nonspecifi cally 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. De Vijlder HC, Westerhof W, Schreuder GM, et al: Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with viti-

ligo is supported by an HLA study, Pigment Cell Res 17:270–274, 2004.

7. What is a congenital nevus? A melanocytic nevus that is present at birth. For the purpose of management, any melanocytic nevus that arises during the fi rst year of life is considered “congenital.” Congenital melanocytic nevi (CMN) are usually characterized as small, large, or giant, although there is no universally accepted defi nition of these categories. Small CMN are usually defi ned 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 classifi cation 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. 41-1 D).

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8. 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 signifi cantly greater risk for melanoma than an acquired melanocytic nevus. The best evidence suggests that there is about a 1% to 4% chance of developing melanoma in CMN � 60 cm. 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 their 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 160:143–150, 2009. 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 160:387–392, 2009.

9. 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 heterogenous 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. 41-2 ).

Blue nevi are usually acquired and have their onset most commonly in childhood and adolescence, but �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 identifi ed varieties of blue nevi are the common blue nevus, cellular blue nevus, and combined blue nevus–melanocytic nevus.

10. Can blue nevi become malignant? Yes. Malignant blue nevi can develop de novo in existing cellular blue nevi, or in a nevus of Ota (see below). Most commonly, the lesion presents as an expanding dermal nodule that may ulcerate. As with other forms of cutaneous melanoma, metastases may develop. Malignant blue nevi are tumors of older individuals. It is more frequent in males then females. The scalp and extremities are the most common sites of occurrence. The prognosis in malignant blue nevi is poor. However, malignant blue nevi are rare, and often there is controversy regarding their histopathologic diagnosis. Zembowicz A, Mihm MC: Dermal dendritic melanocytic proliferations: an update. Histopathology 45:433–451, 2004.

11. What is a combined melanocytic nevus? A combined melanocytic nevus is a blue nevus with an overlying melanocytic nevus. The blue nevus may be a common or cellular blue nevus. The overlying melanocytic nevus can be junctional, compound, or intradermal. This is found in 1% of all excised melanocytic nevi.

12. How does a nevus of Ota differ from a nevus of Ito? The nevus of Ota (also called nevus fuscoceruleus ophthalmomaxillaris) is characterized clinically as a blue to gray hyperpigmentation of the skin, mucosa, and conjunctiva in the distribution of the trigeminal nerve. Less commonly, it may also involve the meninges (meningeal melanocytoma), where it may develop a hemorrhage or, rarely, a malignant melanoma. Histologically, it is composed of heavily melanized dendritic dermal melanocytes in the upper dermis. The nevus of Ito is similar in histology to the nevus of Ota but is distributed along the neck and shoulder in the distribution of the posterior supraclavicular and lateral cutaneous brachial nerves. Both lesions are considered congential dermal melanocytoses and are more common in Asians and African-Americans. About 80% of all reported cases have been woman.

13. What is the best way to treat nevus of Ota? Most lesions are a cosmetic issue only and treatment is not necessary unless it starts to affect the patient’s self-esteem. In the past, scarring treatment modalities such as excision and cryotherapy were utilized. In the last 10 years, the use of Q-switched ruby, alexandrite, and Nd:YAG lasers has markedly improved the cosmetic appearance of these lesions, and they have become the treatment of choice. Although malignant changes are extremely rare, nevus of Ota patients with eye

Figure 41-2. Blue nevus on the lower leg. (Courtesy of Fitzsimons Army Medical Center teaching fi les.)

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involvement should be followed closely, because a majority of associated melanomas occur in the ocular region.

14. What is a Mongolian spot? A Mongolian spot is congenital dermal melanocytoses characterized as a congenital hyperpigmented spot found in the sacrococcygeal region. Most frequently found in black or Asian infants, it also occurs in infants of other races. The pigmentation often improves spontaneously in the fi rst 3 to 5 years of life but may persist to some degree into adulthood. These lesions are believed to represent the delayed disappearance of dermal melanocytes. The deep blue pigmentation is another example of the Tyndall effect. Snow TM: Mongolian spots in the newborn: do they mean

anything? Neonatal Netw 24:31–33, 2005.

15. What is a Spitz nevus? A Spitz nevus is a benign melanocytic nevus named in honor of Dr. Sophie Spitz, who initially described this lesion as a benign juvenile melanoma . These most commonly occur in children but may occur at any age. Spitz nevi are most commonly acquired but as many as 7% may be congenital. The lesion usually presents as a small, pink papule or nodule on the face or lower extremities ( Fig. 41-3 ). Histologically, it is composed of nevus cells that are pleomorphic and cytologically atypical; these cells typically demonstrate a spindle or epithelioid appearance that shares many of the histologic characteristics found in melanoma. The histologic differentiation of Spitz nevus from malignant melanoma is one of the most diffi cult challenges in dermatopathology and, in some cases, the biologic behavior cannot be predicted using current criteria. It is noteworthy that, to date, no B-Raf mutations have been detected in Spitz nevi, in contrast to common acquired melanocytic nevi. A small subset of Spitz nevi demonstrate H-Ras mutations. Sulit DJ, Guariano RA, Krivda S: Classic and atypical Spitz nevi: review of the literature, Cutis 79:141–146, 2007. Takata M., Saida, T: Genetic alterations in melanocytic tumors, J Dermatol Sci 43:1–10, 2006.

16. Where do Becker’s nevi occur? A Becker’s nevus is characterized by an area of hyperpigmentation and often hypertrichosis, most commonly on the upper back, shoulder, or chest of males ( Fig. 41-4 ). The lesions usually become noticeable at puberty. Histologically, there are increased numbers of melanocytes, dermal melanophages, terminal hairs, and hyperpigmentation of the epidermal basal layer. Some lesions can also show increased smooth muscle and have been called smooth muscle hamartomas. Danarti R, Konig A, Salhi A, et al: Becker’s nevus syndrome revisited, J Am Acad Dermatol 51:965–969, 2004.

17. What is a dysplastic (atypical) melanocytic nevus? Dysplastic or atypical nevus is a controversial term that has eluded a precise defi nition. It has been commonly used to describe an atypical-appearing melanocytic nevus believed to have increased potential for malignant transformation. Since this lesion was fi rst described, the atypical nevus has been the subject of controversy. Argument has centered on the criteria for its histopathologic diagnosis, the incidence of melanomas developing in the lesion, and the histopathologic association of melanoma arising in an atypical nevus. Naeyaert JM, Brochez L: Clinical practice. Dysplastic nevi.

N Engl J Med 349:2233–2240, 2003.

18. What is the preferred terminology for dysplastic (atypical) nevi? The terminology used for this lesion is the subject of controversy. The lesion was fi rst described by Clark et al in 1978, and they used the term “B-K mole syndrome” to refer to the presence of multiple melanocytic lesions that had clinically and

Figure 41-3. Spitz nevus. Typical red papule on the cheek of a young child. Because of their red color, they are clinically often mis-taken for vascular neoplasms. (Courtesy of the William L. Weston, M.D. Collection.)

Figure 41-4. A Becker’s nevus on the upper back of a young man. This lesion has no potential for malignant degeneration.

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histologically distinct features in two families at increased risk of developing melanoma. Since then, various terms have been applied to describe this syndrome and its corresponding lesion, including the B-K mole, precancerous melanosis, atypical melanocytic hyperplasia, Clark’s nevus, active junctional nevus, and melanocytic nevus with architectural disorder and cytologic atypia. “Dysplastic nevus” was fi rst coined by Green et al in 1980; however, some authorities have objected to this term and prefer “atypical nevus.” The recognition of atypical nevi in the nonfamilial setting has also been reported and termed sporadic dysplastic (atypical) nevi. More recently, an alternative term for dysplastic (atypical) nevi was proposed by a National Institutes of Health consensus group as “nevi with architectural disorder and cytological atypia.” The conference also recommended replacing atypical nevus syndrome with familial atypical melanocytic nevus syndrome. Despite their recommendations, this terminology has not been universally accepted among clinicians and pathologists. Elder DE: Dysplastic naevi: an update, Histopathology 56:112–120, 2010.

19. What is the clinical relevance of atypical melanocytic nevi? The clinical relevance of atypical nevi relates to their association with increased melanoma risk. Several retrospective and prospective case-control studies have established that increasing numbers of atypical nevi confer an independent increasing risk of melanoma ranging from 2- to 71-fold. Patients with atypical nevi and two or more family members with melanoma seem to be at the highest risk for melanoma. Evidence that atypical nevi may be potential precursors of melanoma includes photographically documented examples of change in a preexisting nevus and the observation of histological atypia in proximity to melanomas. About 25% to 50% of melanomas have a histologically associated nevus, and the incidence rate of melanomas arising in association with atypical nevi has been estimated to be �0.5% to 46%. The most convincing evidence for this association is the demonstration of similar or identical genetic changes in a melanoma and its associated nevus.

Despite the above fi ndings, as well as the documented increased risk of melanoma in patients with atypical nevi, it is important to recognize that most atypical nevi are benign and do not progress to melanoma. In this regard, previous studies have shown that anywhere from 20% to 40% of melanomas arise from a preexisting nevus, 30% to 70% arise de novo and, in almost a quarter, the historical origin cannot be assessed. Therefore, although there is a clear association between nevi and melanoma risk, at present it is not clear whether an atypical nevus is more likely to develop into a melanoma than any other type of nevus. Moreover, it is quite clear that a nevus precursor is not required for the majority of melanomas. It is thought that the discrepancy between melanomas arising in preexisting nevi and de novo melanomas can best be explained by the cancer stem cell theory. In this regard, the risk of melanoma associated with nevi may be due to the potential for secondary mutations within nevi, as well as due to the inherent properties of the stem cell population in individuals with numerous moles.

20. Describe the genetic mutations found in atypical melanocytic nevi. Mutations in susceptibility genes have been detected in atypical nevi including cyclin-dependent kinase inhibitor 2A ( CDKN2A ) and cyclin-dependent kinase 4 ( CDK4 ). Furthermore, a high incidence of B-Raf mutations has also been detected in atypical nevi. It is thought that these mutations may be due to ultraviolet radiation because patients with atypical nevi may have a decreased ability to repair ultraviolet light–induced DNA damage. Weatherhead SC, Haniffa M, Lawrence CM: Melanomas arising from naevi and de novo melanomas: does origin matter? Br J Dermatol

156:72–76, 2007.

21. How common are atypical melanocytic nevi? The exact incidence is unknown, but it is estimated that 2% to 8% of the population have one or more atypical nevus.

22. Is there a difference between an atypical nevus and melanoma in situ? Yes. The difference is determined by the histopathology. Unfortunately, consensus regarding the histologic defi nition of atypical nevi is lacking. When an atypical nevus has atypical melanocytic nevus cells at the dermal–epidermal interface, some of these cells may exhibit cytologic atypia, but this is variable and not continuous throughout the lesion. There are also often architectural abnormalities noted between melanocytic nests. In contrast, melanoma in situ has atypical melanocytes, both singly and in small nests scattered through all levels of the epidermis (pagetoid pattern). Further, a typical melanoma is often more asymmetrical; melanocytes present as solitary units in the epidermis rather than in nests, and the melanocytes demonstrate a greater degree of cytologic atypia.

23. What is the recommended treatment for an atypical nevus and melanoma in situ? Recommended treatment for melanoma in situ is complete full-thickness excision with a minimum of a 0.5-cm margin of normal skin. However some studies suggest that 0.5 cm may be not be the optimal margin for melanoma in situ. Controversy exists regarding the treatment of atypical nevi. Depending on the degree of cytologic atypia, full-thickness excision with margins ranging from 0.2 to 0.5 cm have been recommended. However, for atypical nevi with mild to moderate degrees of cytologic atypia, the question of complete excision is controversial. The latter refl ects the lack of consensus about the grading of atypia in nevi, as well as the insuffi cient data regarding the signifi cance of melanocytic atypia in nevi. It should be stressed that the removal of large numbers of atypical nevi results in signifi cant scarring. Only after thorough evaluation, and when a melanoma cannot be ruled out, should surgical removal be performed. As mentioned above, the vast majority of atypical nevi never become melanomas.

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24. Describe the clinical appearance of atypical nevi. No single feature is diagnostic of atypical nevi; instead, a collection of clinical fi ndings is required for their diagnosis. Atypical nevi are usually larger than ordinary nevi (�6 mm) and have slightly irregular borders that fade into the surrounding normal skin ( Fig. 41-5 ). Variation of color with an asymmetrical pattern is common. The colors vary from shades of brown to black, tan, and light red. The lesions typically have a dark center surrounded by pigment that has poor margination. Atypical nevi most frequently are located on the trunk, scalp, breast (in women) and bathing-trunk areas (in men).

25. Is there a difference between a liver spot and a freckle? Yes. Liver spot is the term commonly used to refer to a solar or senile lentigo. A lentigo is a hyperpigmented (usually brown or black) macule that is characterized histopathologically by increased numbers of melanocytes at the dermal–epidermal junction and increased amounts of melanin in both the melanocytes and basal keratinocytes. These lesions commonly arise on the dorsal aspects of the hands and face. Although solar lentigines are induced by ultraviolet radiation, they do not increase in pigmentation with exposure to the sun. Polymorphisms in the melanocortin receptor 1 gene ( MCR1 ) have been associated with the development of freckles. Freckles (ephelides) are hyperpigmented macules limited to sun-exposed skin. Microscopically, they show increased amounts of melanin in basal keratinocytes, but not increased numbers of melanocytes. Freckles characteristically darken with sun exposure and lighten when the affected areas are protected from ultraviolet radiation.

A B

Figure 41-5. Atypical nevi. A, Patient with familial atypical melanocytic nevus syndrome demonstrating numerous atypical nevi. B, An atypical nevus demonstrating marked variegation in color and loss of normal symmetry.

Key Points: Benign Melanocytic Tumors

1. Benign melanocytic nevi may arise, grow, and regress normally. Rapid change is not normal. 2. There appears to be a small increased risk (1% to 4%) of melanoma in patients with giant CMN. 3. Patients with a large number (�100) of atypical melanocytic nevi should be followed closely for the possible development of

melanoma. 4. Between 30% and 70% of malignant melanoma arise de novo independent of a preexisting nevus. 5. Mutations in CDKN2A , CDK4 , and B-Raf have been detected in atypical nevi. 6. Multiple CALMs are most commonly associated with neurofi bromatosis. 7. Ephelides and lentigines are not melanocytic nevi.

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26. What is a café-au-lait macule? Café-au-lait macules (CALMs) are uniformly light-brown (the color of coffee with cream) macules that vary in size from 2 to 20 cm and often have irregular borders. They are characterized by increased melanin in both melanocytes and keratinocytes and by giant melanosomes. CALMs grow proportionately to body growth and remain stable in size after body growth has completed. CALMs are found in 10% to 20% of the general population; however, multiple CALMs are relatively rare (0.25% to 0.5%) in the general population and should alert you to the possibility of an associated disease. Multiple CALMs are most commonly associated with neurofi bromatosis (see Chapter 5 ), and large CALMs with the McCune-Albright syndrome (see Chapter 18 ). Landau M, Krafchik BR: The diagnostic value of café-au-lait macules, J Am

Acad Dermatol 40:877–890, 1999.

27. What is a nevus spilus? A nevus spilus is an irregularly shaped, light-brown macule with darkly pigmented macules or papules scattered randomly within the macule ( Fig. 41-6 ). The light areas demonstrate the microscopic changes of a café-au-lait macule, and areas of increased melanin with darker pigmentation show the histology of lentigines or junctional nevi. Rare cases have developed malignant melanomas. Vaidya DC, Schwartz RA, Janniger CK: Nevus spilus, Cutis 80:465–468,

2007.

28. Can melanocytic nevi arise in locations other than the skin? Yes. Melanocytic nevi can occur on the retina, conjunctiva, and oral (and other) mucosal surfaces.

29. What is a labial lentigo? Labial lentigo (labial melanotic macule) is a hyperpigmented macule that develops on the lip. Seen most commonly in young women, there is thickening of the epidermis and increased melanin in the basal keratinocytes. These typically behave in a benign fashion.

Figure 41-6. Nevus spilus showing a large café-au-lait macule with multiple small pigmented lesions.