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Common (also called typical) acquired nevomelanocytic nevi develop after birth, slowly enlarge symmetrically, stabilize, and after a period of time may regress. The majority of common acquired nevi appear to develop during the second and third decades of life, although some lesions may appear in the first 3–6 months of life.
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A number of studies have quantified the number of typical acquired nevi in different age groups. In 432 European whites between the ages of 4 days and 96 years, nevi that were 3 mm in diameter or larger were detected in females and males, respectively, at median numbers of 0 and 2 in the first decade, 10 and 16 in the second decade, 16 and 24 in the third decade, 10 and 19 in the fourth decade, 12 and 15 in the fifth decade, 4 and 12 in the sixth decade, and 2.0 and 3.5 in the seventh through the ninth decades.24 In a series of Australian whites, the average number of nevi per person peaked at 43 for males and 27 for females during the second and third decades, respectively, and decreased to very few in the sixth and seventh decades.25 A similar age-related prevalence rate for nevi has been documented in other countries. A difference in frequency distribution of nevi according to gender is not clear, although most series show a close to equal prevalence in males and females.
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The prevalence of acquired nevi varies according to ethnicity. In African blacks, the overall prevalence of nevi (regardless of size) tends to be higher in those with lighter skin versus those with darker skin.26 When prepubertal whites were examined for nevi, a significant association for excess nevi was documented for pale skin, blue or green eyes, blond or light-brown hair, and a tendency to sunburn, but not a tendency to freckle.27 Other studies show variable relationships to these same parameters.
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Environmental exposure to UVR appears to be a critical permissive or inciting factor for the development of nevomelanocytic nevi. In an Australian study, nevus density has been shown to increase with increasing sun intensity in the northern parts of the continent.28 Furthermore, the use of UVR-blocking sunscreens has been shown to decrease the number of new nevi in children.29
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Genetic factors appear to play a role in the development of nevomelanocytic nevi. The size, frequency, and distribution patterns of acquired nevi tend to aggregate in families. This observation is well documented for atypical nevi in the setting of familial cutaneous melanoma (see Chapter 123) and CNN.
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Acquired nevi may be attacked by the patient's immune system, resulting in the development of a halo nevus (see Section “History”). Of 8,298 whites aged 12–16 years, there were 51 males (1.2%) and 22 females (0.5%) who had one or more halo nevi, for an overall prevalence rate of 0.9%.30 In one large series of halo nevus,31 individuals ranged in age from 3 to 42 years (mean age, 15 years), with the vast majority of cases occurring before age 20 years. The halo phenomenon has been associated with prominent numbers of common nevi, prominent numbers of atypical nevi, and CNN both small and large.
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Etiology and Pathogenesis
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There has been an ongoing debate as to the origin of nevomelanocytic nevi. Although many theories have been proposed, and some supporting data are available, the critical events leading to nevus development remain a mystery. Although data suggest that nevomelanocytic nevi are clonal,32–34 the B-RAF35 mutation that is present in the majority of common acquired (including atypical) nevi appears to be polyclonal36 suggesting that B-RAF mutation is either a secondary event or that nevomelanocytic nevi can incorporate multiple precursors. Melanocytic “precursor” cells have been shown to be present in adult human skin37 and melanocytic stem cells have been identified in the mice.39 It is assumed that these melanocytic stem cells accumulate mutations, and when needed to replenish melanocytes, they produce nevomelanocytes instead. Presumably, these nevomelanocytes then attempt to migrate along normal developmental pathways from the dermis into the epidermis. Dependent on the underlying mutation, some cells might also migrate aberrantly. The defect, timing, and local tissue influences could allow for the creation of a variety of different melanocytic neoplasias.38
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The clinical phenomenon of eruptive nevi also further confounds the location of the cell of origin issue. In these patients, there is the abrupt appearance of numerous similar appearing nevi often in the setting of immunosuppression or chemotherapy. Although it is generally assumed that these lesions all directly originate in the skin, drawing a comparison with epidermotropic metastatic melanoma leaves open the possibility of a circulating nevomelanocytic precursor.
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Acquired nevi primarily develop during childhood and early adulthood. Although nevi can clearly persist in a stable state for decades, many eventually regress. In a study following patients with dysplastic/atypical nevi, the highest rate of nevus development and nevus regression was present in patients younger than 30 years of age.40 In later adult years, nevus counts are significantly less than those in young adulthood, and the rate of new or growing nevi declines, while melanoma incidence increases. Thus, a growing lesion in an older adult has a greater risk of being melanoma although new or changing moles still significantly outnumber melanomas.40
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Spontaneous and concurrent development of scattered nevomelanocytic nevi often similar in appearance has been termed eruptive nevi. Often, these patients have experienced a blistering skin disease, immunosuppression, cytokine administration, or chemotherapy. Eruptive nevi may have a pattern consistent with common acquired nevi, but Spitz nevi and blue nevi have also been described.
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Patients may also present with the history of spontaneous development of a zone of depigmentation around a preexisting nevus. This phenomenon has been called a halo nevus. The halo phenomenon may be associated with acquired and CNN as well as with melanoma and nonmelanocytic tumors. This phenomenon often, but not always, indicates the onset of involution and subsequent regression of the melanocytic nevus. Other names for this phenomenon include leukoderma acquisitum centrifugum, Sutton's nevus, leukopigmentary nevus, perinevoid vitiligo, and perinevoid leukoderma. Time for full evolution to depigmentation of the halo is not known, but patients report the phenomenon occurring over days to weeks, with little change occurring in the halo thereafter. The central nevus may persist or eventually disappear. Disappearance may take months to years. Areas of depigmentation that remain after the central nevus disappears may remain stationary for many years or repigment after months to years. There are lesions in which the nevus does not involute, and repigmentation of the depigmented halo may occur. Halo may be associated with depigmentation at other sites, and the depigmentation may resolve when the CNN is excised (see Fig. 122-10).
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Common acquired nevi vary considerably in their gross appearance. In general, appearance to the naked eye is orderly: the lesions have a homogeneous surface and coloration pattern, round or oval shape, regular outlines, and relatively sharp borders (Fig. 122-9). Common acquired nevi may be papillomatous, dome-shaped, pedunculated, or flat-topped and are usually skin-colored, pink, or brown. More elevated acquired nevi tend to be more lightly pigmented, and flatter acquired nevi tend to be more darkly pigmented. More elevated and less pigmented lesions tend to have a prominent intradermal nevus component, whereas flatter and darker lesions have a more prominent junctional melanocytic or nevomelanocytic component and a less prominent dermal component. Very dark brown and black are unusual colors for common acquired nevi in lightly pigmented people. In contrast, dark pigmentation is usual for common acquired nevi in people who have darkly pigmented skin. Blue, gray, red, and white areas in a nevus are not typical features and ought to be viewed with suspicion. The surfaces of nevi may reveal hair that is less than, equal to, or greater than that of surrounding skin. Hair in nevi may be coarser, longer, and darker than that in surrounding skin (often these lesions reveal congenital features). Lesions on palms and soles are usually hairless. Size, shape, skin markings, and hair quality of nevi in darkly pigmented persons are similar to those in whites.
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Dermoscopy reveals a number of diagnostic patterns in common acquired nevi. In general, these lesions reveal a reticular or globular pattern. On the palms or soles, a parallel-furrow, lattice, or fibrillar pattern may be present. Nonuniform patterns and parallel-ridge patterns are worrisome for melanoma.
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Pigmented nevi of the nail apparatus may be a dark or light brown, extending from the nail matrix to the distal edge of the nail plate (see eFig. 122-9.1); extension of the pigmentation onto the skin of the nail fold or beyond the distal nail groove should be considered suspicious for melanoma. Nevi on palms and soles, even compound nevi, may not distort the skin surface, perhaps because of a thickened stratum corneum in these sites.
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The typical halo nevus has a pink or brown central nevomelanocytic nevus surrounded by a symmetric round or oval halo of depigmented skin. The central nevus may be small in typical acquired nevi, or large in acquired atypical or congenital nevi (Fig. 122-10). The halo of depigmentation is variable in size, usually a radial zone 0.5–5.0 cm around the central lesion. White hairs may be seen in hair-bearing depigmented areas. Alopecia areata surrounding a halo nevus has been reported. The number of halo nevi per person may be one or many, multiple lesions occurring in 25% to 50% of patients. For patients who have multiple lesions, only a few nevi are usually affected, but as many as 90 halo nevi have been reported in a single person. Any nevus in any anatomic site may be involved, but the posterior torso is involved most commonly. Lesions are usually asymptomatic. UVR may cause redness and even blistering in the perinevic halo. An atypical gross appearance of the central nevus or an asymmetric halo of depigmentation around a suspicious nevus, particularly in adults, should raise suspicion for melanocytic dysplasia or melanoma. The depigmented halo associated with melanoma tends to be irregular and surrounds the tumor asymmetrically, and the central lesion usually has an atypical appearance. Unfortunately, this appearance is not always the case and a high index of suspicion for melanoma must be maintained in patients who have prominent numbers of atypical nevi (with or without melanoma) and also have halo nevi.
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A second process that may provide some insight into factors involved in melanocytic interactions with the immune system is a process that results in the development of an eczematous dermatitis presenting as a red halo around nevi (halo dermatitis, Meyerson's nevus). Unlike halo nevi, regression of the nevus does not usually occur, and the eczematous changes clear over the course of several months.
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Related Physical Findings
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For patients with multiple nevi, there is an increased risk for cutaneous melanoma (see Chapters 123 and 124). This risk is further increased in the setting of atypical nevi and/or a personal or family history of melanoma. For patients with eruptive nevi, there may be findings suggestive of a blistering disease or immunosuppression. For patients with halo nevi, the most common associated condition is vitiligo, occurring in 18% to 26% of patients. Halo nevus may be associated with poliosis, Vogt–Koyanagi–Harada syndrome, pernicious anemia, prominent numbers of nevi, atypical nevi, and a personal or family history of melanoma (including ocular melanoma). Relatively large and numerous nevi are common in Turner syndrome and Noonan syndrome.
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Nevomelanocytes in the epidermis have a nuclear size similar to or larger than nuclei of epidermal melanocytes. Epidermal nevomelanocytes are arranged in nests surrounded by a smooth perimeter of epidermis, and the epidermis is separated from nevomelanocytes by a retraction artifact (Fig. 122-11). Nevomelanocytes have abundant pale-staining eosinophilic cytoplasm and may have pseudopodic or dendritic extensions that are more evident when enzymatic or immunohistochemical techniques are used for visualization. Nuclei of nevomelanocytes are pale-staining, characterized as vacuolated or reticulated; a nucleolus is usually visible.41 Epidermal melanocytes between junctional thèques of nevomelanocytes in typical nevomelanocytic nevi are disposed as single typical cells, with overall numbers equal to or slightly greater than that in adjacent sun-exposed skin (see Fig. 122-11).42 The overlying epidermis is often normal in appearance but may be thickened in a lentiginous pattern (elongated and club-shaped rete ridges), with an appearance similar to seborrheic keratosis complete with horn cysts or epidermal verrucous hyperplasia similar to epidermal nevus.
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The dermal component of nevi has an orderly progression from top to bottom, with larger epithelioid cells above (epidermis and superficial papillary dermis) blending into a pattern of smaller cells in the deeper dermis.
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Nevomelanocytes in the epidermis and upper papillary dermis frequently resemble epithelial cells, with an oval or cuboidal shape, a well-outlined cytoplasm that is homogeneous in character, a nucleus not much larger than nuclei of basal keratinocytes, and a visible nucleolus. In the epidermis and superficial dermis nevomelanocytes frequently contain small amounts of melanin. In the middle or deep dermis they are usually smaller than nevomelanocytes in the superficial dermis or epidermis and frequently resemble lymphoid cells. Nevomelanocytes in the deep dermis may be round or oval and often resemble Schwann cells or fibroblasts when they are singly disposed and may be difficult to differentiate from fibroblasts unless they are disposed in sheets, cords, or patchy aggregates (see Fig. 122-11).43 Usually, dermal nevomelanocytes are interposed among collagen bundles, and there is no distinct rim of collagen or retraction artifact between surrounding collagen and cellular aggregates. Nevomelanocytes in the dermis of typical acquired nevi have a monotonous similarity one to another within the same anatomic level and an overall symmetry of architecture from top to bottom and side to side.
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Some acquired lesions are found to have congenital features (reviewed in Section “Congenital Nevomelanocytic Nevi”) suggesting that though these features may be present in congenital nevi, they are not limited to those present at birth. Other acquired nevi may be found to have atypical features (see Chapter 123).
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Inflammatory cellular infiltrates in typical, stable acquired nevi are usually scanty41 or absent. Melanin-laden macrophages are usually apparent in the superficial papillary dermis of nevi, their number usually proportional to degree of melanin production.41 Blood vessel proliferation, eosinophilic fibrosis, and lamellar fibroplasia (features frequently seen in atypical melanocytic nevi) are usually not prominent in typical acquired nevi. Langerhans cell density overlying typical acquired nevi and atypical nevi is increased compared with adjacent skin.44
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Intradermal nevi that have few or no junctional nests frequently have a grenz zone relatively free of nevomelanocytes just below the epidermis (see Fig. 122-11).
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Multinucleated nevomelanocytes occur occasionally and may be interpreted as a sign of benignity. Nevomelanocytes in the deep dermis may be disposed within a collagenous framework that is loose, pale, and wavy in formations called neuroid tubes, similar to a neurofibroma; they may be disposed in concentrically arranged whorls resembling Meissner's tactile corpuscles; and they may be spindle-shaped and embedded in loosely arranged connective tissue (neural nevi). Both neural nevi and neurofibromas show nonspecific cholinesterase activity. Myelin basic protein is detected in various neural tumors but not in melanocytic or nevomelanocytic tumors, and melanosomes are present in nevomelanocytes but not in neurofibromas or nerve tissue. Cutaneous neural lesions may be distinguished from melanocytic tumors by the presence of myelin basic protein and neurofilaments, and the absence of vimentin.
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The balloon cell nevus is composed of peculiar foam cells comprising a portion or all of a given lesion. In addition to clear cells with single basophilic nuclei, multinucleated balloon cells and multinucleated giant cells are seen frequently. Electron microscopic studies suggest that vacuolization of nevomelanocytes in balloon cell nevi is due to enlargement and destruction of melanosomes. There appears to be no distinguishing gross features of balloon cell nevi.
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The combined nevus refers to the incontiguity association of different types of melanocytic nevi. Most combined blue nevi are found in association with a benign compound nevus (acquired or congenital).
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Recurrent melanocytic nevus (pseudomelanoma) is the name given to recurrent lesions after incomplete removal of a benign nevomelanocytic nevus.45 Recurrent nevi are relatively common after superficial destructive procedures (i.e., shave biopsy or dermabrasion). A markedly atypical clinical and histopathologic appearance may accompany this recurrence, making these lesions worrisome for possible melanoma. Clinically, the recurrent nevus is confined to the scar but may be markedly irregular. Histopathologically, recurrent lesions often demonstrate melanocytic hyperplasia in a lentiginous or junctional pattern (often to a greater extent than the original nevus). Moderate nuclear atypia may be present in 12% of recurrent nevi, mitotic figures in 8%, and pagetoid upward migration in 3%, raising concern about the potential biologic behavior of some recurrent lesions.46 It is important to review the original histopathologic specimen when making re-excision and margin decisions.
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No definitive and consistent histopathologic features have been described for eruptive nevi.
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For halo nevi, the usual histopathologic findings are a central nevomelanocytic nevus associated with a dermal band-like lymphohistiocytic infiltrate and a depigmented zone totally or almost totally devoid of epidermal melanocytes. Immunohistochemical staining—melanoma antigen recognized by T cells (Mart-1), S100 protein, or other melanocytic markers—may help to identify residual epidermal melanocytes or the nevomelanocytes in the inflammatory infiltrate. Lymphocytes in halo nevi appear to be antigenically stimulated, and 80% are T lymphocytes, whereas B lymphocytes are scarce or absent. The T cells appear to belong to the CD8+ phenotype.47
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Other findings have been identified in nevi that may suggest modes of regression or elimination of melanocytic elements. Some of the findings include neuroid, fibrous, mucinous, and fatty degeneration.48 Nevomelanocytes in the stratum corneum49 represent transepidermal elimination. Psammoma bodies and amyloid bodies, present occasionally in nevi, also may be related to degeneration or regression. Fibrosis may occur as an age-related phenomenon, whereas true desmoplasia appears to be a reactive process or functional transformation by the nevomelanocytes. Follicular mucinosis has been reported in nevi in at least two cases. Spicules of bone are observed occasionally in nevi, possibly related to reactive metaplasia, trauma, or infection.
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Histopathologic artifacts may occur in nevomelanocytic nevi. Shrinkage clefts may resemble lymphatics or vascular spaces, prominent in the midportion of nevi and particularly in areas with hemorrhage. Separation of sheets of nevomelanocytes into parallel rows may be caused by improper cutting. Local anesthesia injection directly into the nevus also may be associated with artifactual changes.
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The state of the nevus at the time of excision may also influence the histopathologic appearance. Nevi acutely sunburned or traumatized may have features worrisome for melanoma, and these changes resolve over a short time period.50 Nevi in a rapid growth phase also may have atypical features such as epithelioid cell appearance and pagetoid upward migration, but these observations require corroboration.
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Worrisome features for possible melanoma include pagetoid upward migration of cells in the epidermis, atypical features of epidermal melanocytes [including irregularity of size and shape of cells, condensation of chromatin on nuclear membranes, a heterochromatin (clumping) pattern], failure of the cells to “mature” in the deeper dermis, persistence of pigment production in the deep dermis, lack of symmetry, frequent mitotic figures, focal areas of necrosis, and desmoplasia or fibrosis in the dermis.
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Special tests are not generally required in the gross and microscopic assessment of melanocytic or nevomelanocytic nevi. However, for patients who have eruptive nevi, given the association with immunosuppression, immunologic tests may be in order. Immunohistochemical profiles may be of value for difficult to diagnose lesions. Low Ki67 activity and loss of HMB45 in dermal (deeper) cells may help confirm a benign diagnosis. Compared to melanoma, common acquired nevi are genomically stable.51 FISH (fluorescence in situ hybridization) or CGH (comparative genomic hybridization) analysis may ultimately be useful in discriminating benign lesions from lesions with a metastatic tendency.
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Multiple studies demonstrate that prominent numbers of nevi indicate an increased melanoma risk. Tucker et al52 noted a 3.4 (95% confidence interval: 2.0 to 5.7) adjusted relative risk for patients with 100 nevi or more (>2 mm and <5 mm) compared with those with fewer than 25 nevi. The relative risk was increased to 12 (95% confidence interval: 4.4 to 31.0) for patients with ten or more atypical nevi compared with patients without atypical nevi. Absence of direct site specificity of nevi and melanoma suggests that nevus proneness per se indicates a general melanoma risk,53 largely independent of hair and eye color and overall sun exposure.54 Other traits, including skin color and freckles, may be multiplicative to the number of nevi in increasing melanoma risk.55 The annual risk of a melanoma developing in a mole has been calculated to be approximately 1 in 200,000.56 Furthermore, it has been reported that only 26% of melanomas are found in association with nevus elements.57 Thus, it is likely that the majority of melanomas develop directly from normal skin (see Chapter 124). In patients with numerous nevi (and/or atypical nevi) these nevi are best viewed as risk markers, not precursors (or precancers) of melanoma.
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Prognosis and Clinical Course
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It is likely that acquired nevi evolve through a life cycle, first becoming apparent after infancy in the vast majority of cases, peaking in number during the second and third decades of life, and then disappearing by the seventh to ninth decades.24,25,48 Regression of nevi is believed to occur by neuroid, fibrous, mucinous, or fatty degeneration.47 Transepidermal elimination of nevomelanocytes has also been noted.49,58 Nevi also may involute during the course of inflammatory halo depigmentation (halo nevi). The pathogenesis of the halo phenomenon is poorly understood. Available evidence suggests that both humoral and cellular factors may be responsible for nevus destruction in halo nevi. Atypical nevi, melanoma, and vitiligo may occur more frequently in individuals with halo nevi.
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Eruptive nevi occur as the spontaneous appearance of multiple nevomelanocytic or melanocytic nevi. These nevi are often similar in appearance to each other clinically and histopathologically. Reports generally link the initiating event to a blistering skin disease, systemic immunosuppression, chemotherapy, or treatment with “biologics.”59 The setting allowing for eruptive nevi may also predispose to melanoma development, as reported for some transplant patients. Patients who have eruptive nevi need to be monitored carefully.
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There may be relatively sudden changes in nevi that are unrelated to malignant transformation. Any single nevus that is noted to suddenly change independently should be cause for concern. Causes of sudden changes in a nevus (color, surface, or size, with or without pain, itching, ulceration, or bleeding) over days or weeks include cystic dilatation of a hair follicle, epidermal cyst formation, folliculitis, abscess formation, trauma, hemorrhage, and, in the case of a pedunculated nevus, strangulation and thrombosis. These benign causes of sudden change may require close observation for several weeks until resolution occurs, or excision for histopathologic examination.
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The vast majority of acquired nevi are harmless. New nevi may continue to appear and disappear throughout life, but most develop during childhood and early adulthood. New or growing nevi in older individuals are more worrisome. Melanoma risk appears to be related to the number and size of nevi; patients with numerous nevi, atypical nevi, and a personal or family history of melanoma should be considered for periodic surveillance examinations for life.
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The vast majority of acquired nevomelanocytic nevi require no treatment. Indications for removal of benign-appearing lesions may include cosmetic concerns or continual irritation. Lesions with worrisome clinical features need to be excised for histopathologic examination. These features are further addressed in Chapters 123 and 124. Dermoscopy may be used to differentiate benign from potentially malignant features. Photographic surveillance can play a critical role in identifying change, or lack of change, in suspicious nevi. All nevomelanocytic nevi have an initial growth phase. Thus, additional factors, such as unusual gross morphologic features, are required for decision-making for any particular lesion.60
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Although a benign-appearing nevus associated with halo depigmentation does not require excision, it is reasonable to recommend periodic examination of affected individuals for atypical melanocytic nevi, vitiligo, and melanoma. Atypical-appearing central nevi, presence of an asymmetric halo, eccentric placement of a melanocytic lesion in the halo, or the setting of atypical melanocytic nevi and/or melanoma (personal or family) suggest the need for histopathologic examination for melanoma. Cover-ups or sunscreens should be recommended for sun-exposed areas of depigmentation to prevent acute burn, chronic actinic damage, and UVR-induced carcinogenesis.
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Complete removal of nevi is best accomplished by excision. Leaving a partially excised nevus, regardless of the initial pathology, is fraught with potentially concerning consequences of repigmentation and/or regrowth (pseudomelanoma).45 Incisional biopsy, even for melanoma, is necessary at times, particularly for lesions that cannot be excised easily but require histopathologic diagnosis. Destructive modes of therapy (electrodesiccation, cryotherapy, dermabrasion, and laser) should be avoided. These destructive modes of therapy preclude histopathologic assessment of the treated nevi. They have the disadvantage of not providing tissue for histopathology. Although dermabrasion has been used to eliminate pigmentation of nevomelanocytic nevi, residual nevomelanocytes in the dermis are to be expected, cosmetic outcome is often unpredictable, and recurrence with worrisome clinical features may complicate future management. Laser treatment of melanocytic and nevomelanocytic lesions has the theoretic risk of malignant transformation, but a clear demonstration of this possibility is still wanting.
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There appears to be a direct relationship between the number of acquired nevi and sun exposure, and a decrease with sunscreen use. While there is no direct cause and effect relation between most cases of melanoma and UVR, patients at increased risk should be encouraged to minimize UVR overexposure without impeding day-to-day activities. Sensible UVR exposure includes confining outdoor activities to the early morning or late afternoon/evening, and avoiding the most intense UVR fluence occurring 2 hours either side of high noon. Cover-up clothing that blocks light transmission should be worn during intense UVR exposure. Clothing is often easier to put on than sunscreen and does not rapidly wear off with swimming or sweating. Effective sunscreens should be used as part of a comprehensive sun-protection program. Vitamin D supplementation should be recommended for patients who diligently practice UVR avoidance and protection.