Chapter 122. Benign Neoplasias and Hyperplasias of Melanocytes

Benign melanocytic proliferative lesions form a spectrum of disorders ranging from a massive accumulation of cells in multiple tissue elements to epidermal foci with a simple increase in epidermal melanocyte number. Here these lesions are separated into melanocytic neoplasias and melanocytic hyperplasias. The term melanocytic neoplasia is used to describe the presence of melanocytic cells in epidermal nests [defined as three or more melanocytic cells in direct contact (also known as thèque)], within the dermis, or in other tissues. The melanocytic neoplasms are referred to as nevi (singular: nevus) and the melanocytic cells forming these nevi are referred to as nevomelanocytes. The term melanocytic hyperplasia is used to indicate increased melanocytes confined to the basal layer of the epidermis.

The specific molecular events causing melanocytic neoplasias and hyperplasias are beginning to be defined. Given the presence of immature (less melanized) cells in many melanocytic neoplasias, it seems likely that specific underlying mutations (such as N-RAS, GNAQ, and B-RAF) disrupt normal melanocytic development and result in accumulation of the nevomelanocytic cells that do not complete typical migration and differentiation. The melanocytic hyperplasias are comprised of epidermal melanocytes at an increased concentration and thus alterations of normal melanocytic homeostatic mechanisms appear to be operative. These alterations could be due to a primary melanocytic defect [such as an ultraviolet (UV)-induced mutation] or homeostatic signaling changes in the local environment (possibly driven by mutations within the local keratinocytes, fibroblasts, or other resident cells).

This heterogeneous group of disorders is currently loosely subcategorized based on clinical features and microscopic characteristics. The neoplasias described include congenital nevomelanocytic nevi (CNNs), nevus spilus, common acquired nevomelanocytic nevi (excluding atypical/dysplastic nevi covered in Chapter 123), blue nevi, pigmented spindle cell nevi (PSCN), Spitz nevi, and nodal nevi. Cutaneous melanoma is covered separately in Chapter 124. The benign melanocytic hyperplasias described in this chapter include lentigo simplex (including agminated lentigines) and solar lentigines.

Epidemiology

The vast majority of CNNs noted at birth are small and singular, and no gender predilection has been demonstrated. The most reliable prevalence rate for CNN in a homogeneous ethnic group was obtained by biopsying all pigmented lesions in 841 white infants examined within 72 hours of birth: of 21 infants with pigmented lesions, 7 babies (0.83% of 841) had a biopsy-confirmed nevomelanocytic nevus.1 According to other studies, the prevalence of CNN appears to be slightly higher in nonwhites compared to whites. Many other series have yielded equivalent results. CNNs of 99 mm or more in diameter occur in only 1 of every 20,000 newborns, and CNNs with a garment distribution occur in only 1 of every 500,000 newborns.2 Familial aggregation has been demonstrated for both large and small varieties of CNN (Fig. 122-1). Discordance for giant CNNs has been demonstrated for identical twins in at least three cases and for nonidentical twins in two cases.

Etiology and Pathogenesis

CNNs represent a developmental abnormality of normal melanocytic development. This is presumably due to a mutation (often NRAS)3 that occurs in a progenitor cell that results in the abnormal extensive accumulation of melanocytic cells along migration pathways during normal development. The events leading to the nevomelanocyte accumulation may also have effects on the surrounding tissue (i.e., increased length/darker hair) possibly due to changes in the local cytokine environment of the nevomelanocytic cells. Clinical findings such as a congenital divided nevus of the eyelid (Fig. 122-2) can give us insight into when these events occur.4 The eyelids form at between 5 and 6 weeks in utero, begin to fuse at about 8 to 9 weeks, and reopen during the sixth uterine month.5 Because of the contiguous nature of this lesion on the upper and lower eyelids, it may be presumed that the nevomelanocytes migrated into this location sometime during or after eyelid fusion but before the eyelids split.

Clinical Findings

(Fig. 122-3)

History

Most CNNs are present at birth; however, there are also rare varieties of relatively large nevomelanocytic nevi (>1.5 cm) that appear for the first time between 1 month and 2 years of life, according to parental observations and corroborated by photographs (tardive congenital nevi). As a child grows, the CNN should grow relatively proportionally6 and continue to “mature.” History of disproportionate growth, especially after 6 months, or change in a nonuniform manner is of concern for possible melanoma. Both small and large varieties of CNNs have been associated with loss of pigmentation, halo depigmentation, and even regression.

Cutaneous Lesions

Although CNNs are on average larger than acquired nevi, for lesions less than 1.5 cm in diameter there is no specific size limitation that can be used to predict reliably whether a given nevus is congenital or acquired. Lesions attaining a diameter of 1.5 cm or more are likely to be congenital, atypical melanocytic nevi, or melanoma.

There is no completely satisfactory way to categorize CNNs as small or large. Definitions have been based on ease of removal and termed small if they can be excised and the wound defect closed primarily without significant deformity. Arbitrary size criteria have also considered small (<1.5 cm; see eFig. 122-3.1), medium (1.5–19.9 cm), and large (≥20 cm). Size, of course, is all relative to the affected anatomic location and the patient. Giant has been variously defined as a lesion as large as the patient's palm if it occurs on the head and neck (and twice that area for other anatomic sites), 30% of the body surface, or 900 cm2 in adults (or smaller if it involves a major anatomic area) (see Fig. 122-4). Depending on the definition used, lesions that are regarded as small or medium in the newborn period may be designated medium or large, respectively, by late childhood or adulthood, given that CNNs appear to grow in proportion to the affected anatomic site.6

The contour of CNNs is usually smooth, regular, and sharply demarcated, and skin markings distort the skin surface at least slightly when assessed by oblique lighting. Some CNNs are relatively hairless. However, coarse, long, darkly pigmented hair may be present at birth, appear within the first year or two of life, or be delayed for several years. Lesions may have a smooth, pebbly, rugose, verrucous, cerebriform, or grossly lobular surface. CNNs with a cerebriform appearance may present as cutis verticis gyrata.

Dermoscopy may reveal a reticular pattern or globular/cobblestone pattern and may be useful in the identification of small foci of melanoma. In large congenital nevi, there can be significant variability in pigmentation and structure, and melanomas may develop in the deep components potentially reducing the utility of dermoscopy in these lesions.

Unique varieties of CNNs may have an atypical appearance and be striking for their haphazard, very dark-brown, black, or blue–black pigmentation or discontinuous pigmentation and poorly demarcated and/or irregular outlines, often associated with atypical histopathologic features. Very darkly pigmented CNNs are distinctly uncommon in whites and should suggest the possibility of atypical histopathologic features. In darkly pigmented infants, CNNs are usually darkly pigmented.

Related Physical Findings

CNNs of the head, neck, or posterior midline, and/or the presence of multiple satellite lesions associated with large CNN may be complicated by underlying cranial and/or spinal leptomeningeal melanocytosis. This phenomenon may be asymptomatic or may give rise to communicating or noncommunicating hydrocephalus, seizures, focal neurologic deficits, mental retardation, or even melanoma. CNNs need not be giant to be associated with this underlying disorder.

There is a significant association between neurofibromatosis and giant CNNs. In a study by Crowe et al,7 3 of 223 patients with neurofibromatosis had extensive CNNs. In his monograph on neurofibromatosis, von Recklinghausen described 1 of 28 patients as having a giant CNN.8 Tumors indistinguishable from neurofibroma in the absence of von Recklinghausen neurofibromatosis may develop in association with giant varieties of CNN.

Malignant degeneration of large CNNs may be associated with the relatively sudden appearance of a dermal or subcutaneous nodule, very dark pigmentation, itching, pain, bleeding, or ulceration. Often, CNN-associated melanomas appear to have evolved in nonepidermal locations.9 Therefore, early detection of melanoma in association with a giant CNN may be difficult and not recognized until a dermal nodule or metastatic disease appears. The prognosis for patients who develop melanoma in association with giant CNNs is usually grave.9 Unlike melanoma in general, there is no ethnic predilection for melanoma developing in giant CNN. There have been multiple cases of lethal melanoma developing in association with small, medium, large, and giant CNNs in black children.

Laboratory Tests

Histopathology

CNNs are characterized by the presence of nevomelanocytes in the epidermis as well-ordered thèques and/or nevomelanocytes in the dermis, which are present as sheets, nests, cords, and/or single cells. Although histopathologic features are cited as being useful in distinguishing nevi as congenital or acquired, there are no known features with absolute specificity and sensitivity. The histopathologic features of very large CNNs may be divided into nevomelanocytic, neuroid, epithelioid cell and/or spindle cell, blue, and mixed types.

In the nevomelanocytic type of large CNN, the histopathologic appearance may be identical to typical acquired nevi, with nevomelanocytes in the epidermis as well-defined thèques and/or nevomelanocytes in the papillary dermis as sheets, cords, or nests. CNNs are more likely than acquired nevi to have nevomelanocytes in the lower two-thirds of the reticular dermis and to be associated with appendageal and neurovascular structures (Fig. 122-5). There may be preferential involvement of one or more appendageal structures in CNN, such as eccrine ducts, and these structures may be abundant and malformed. Veins may be preferentially involved, with an “inflammatory” appearance showing nevomelanocytes within and around blood vessel walls. Subendothelial protrusion by nevomelanocytes in lymphatic vessels may be prominent. Arrector pili may be malformed, large, and infiltrated by nevomelanocytes. Hair follicles are often quite large and frequently associated with abundant melanin in the hair bulb. Nevomelanocytes in the deep reticular dermis may be distributed as single cells or as a single-file array insinuating among collagen bundles, sheets of cells, or combinations of patterns.

In the neuroid type of giant CNN, melanocytic elements take on the appearance of Wagner–Meissner corpuscles (lames foliacée), a palisaded arrangement of cells around a cellular mass of homogeneous material (Verocay body), and sheathing of nerves by neuroid tissue (neuroid tubes). The neuroid type of nevus may be responsible for lobulation and redundancy of tissue (pachydermatous or cerebriform appearance) due mainly to the production of connective tissue elements such as reticulin, collagen, and sometimes mucinous stroma. The neuroid type of giant CNN may take on the appearance of a pigmented neurofibroma and may be associated with congenital anomalies of bone (club foot, spina bifida, and atrophy) as well as with a “neurosarcomatous” morphologic variant of melanoma.

In the spindle cell and/or epithelioid cell type of giant CNN, the dermis may be infiltrated in whole or in part by nests or sheets of epithelioid cells and/or spindle cells. Unlike the usual variety of acquired epithelioid cell and/or spindle cell nevus, the epithelioid and spindle cell elements in CNN may involve deep reticular dermis, often intermixing with neuroid elements and ordinary nevomelanocytes. The epithelioid cell and/or spindle cell elements in giant CNN may have atypical cellular and architectural features, making differentiation from melanoma extremely difficult. In some cases, large epithelioid cells may comprise superficial papillary zones of the nevus, and smaller nevomelanocytes may appear in the same lesion in deeper zones of the reticular dermis, with a grenz zone separating the two elements.

In the blue (dermal melanocytic) type of giant CNN, the appearance may be that of a giant blue nevus, or the lesion may have elements of blue nevus (either common or cellular type) with heavily pigmented spindle-shaped melanocytic cells alone or intermixed with nevomelanocytes in the reticular dermis or deeper tissues. There may be some biologic overlap with nevus of Ito/Ota and Mongolian spot.

Unique to the very large CNN is the occasional presence of nevomelanocytes within the substance of muscle, bone, placenta, umbilical cord, cranium, and dura mater. Very extensive CNN may be intermixed with elements of vascular malformation, hemangiomas, increased numbers of mast cells, cartilage, calcification, and even bone. There may be sparse mononuclear cell infiltrates associated with some giant CNNs. In addition to melanoma, associated tumors developing in CNN include schwannoma, neuroid tumor, lipoma, rhabdomyosarcoma, neurofibroma, sebaceous nevus, hemangioma, lymphangioma, and mastocytoma. A possible explanation for these mixed neoplasms containing melanocytic, neuronal, and other elements is that the CNN precursor cell, at least in some cases, is a pluripotent stem cell that has the capacity to give rise to multiple cell types.

In giant CNNs, nevomelanocytes have been found in regional lymph nodes without further evidence of progressive metastatic disease. Whether this deposition occurred during the migration of the cells through the dermis or was secondary to migration from the skin after the neoplasm developed is unknown. The presence of nevomelanocytes in the nodal tissue from these lesions does not imply malignancy (see Section “Nodal Nevi”).

CNNs may also give rise to proliferative nodules that may be difficult to differentiate from melanoma.10

Special Tests

For patients with concern of possible leptomeningeal involvement, magnetic resonance imaging should be considered. For patients with concern of melanoma metastatic, positron emission tomography scan may be considered.

Differential Diagnosis

(Box 122-1)

Complications

The relationship between melanoma and large CNNs is well documented. The risk of melanoma development appears to be proportional to the size of the congenital nevus. The cumulative 5-year risk has been calculated to be 2.3%11 and 5.7%12 in patients with congenital nevi that involve over 5% of the body surface. The lifetime risk of melanoma for patients with very large CNNs has been estimated to be at least 6.3%, based on a questionnaire follow-up study of 151 persons with CNNs examined between 1915 and 1973 in Denmark.13 Melanoma may develop in large CNNs at any time, but the diagnosis of melanoma was established in the first 3–5 years of life in approximately one-half of published cases in which patients ultimately developed melanoma in association with giant CNN.

A causal association between small CNNs and melanoma is more difficult to establish than for large CNNs. When histopathologic features were studied, 6% to 8% of primary melanomas were found to be in contiguity with nevi that had microscopic features characteristic of CNN.14,15 These findings support the concept of melanoma risk even with small congenital nevi, given the expected chance association based on body surface area considerations.16

For cranial, midline, or CNN with multiple satellite lesions, there is a risk of leptomeningeal involvement. Symptomatic leptomeningeal melanocytosis carries a poor prognosis, even in the absence of malignant degeneration.

Prognosis and Clinical Course

CNNs have a dynamic evolution during body growth. CNNs at birth usually distort the skin surface at least slightly when assessed by oblique lighting and may become more elevated over time. Surface pigmentation also may change. Lightly pigmented CNNs may become more darkly pigmented, and darkly pigmented CNNs eventually may become less pigmented. CNNs may also develop a halo of depigmentation, potentially heralding spontaneous regression. Loss of pigmentation has been associated with regression of underlying nevomelanocytes and the replacement with sclerosis in some cases. Relatively hairless CNNs at birth may develop long, dark, coarse hair, or may maintain a relatively normal hair density. With few exceptions, CNNs generally expand in direct proportion to growth of a given anatomic zone, although disproportionately rapid area expansion of some congenital nevi may occur during early infancy.6 Lesions in fully grown individuals should remain stable.

Treatment

The treatment of CNNs, large and small, depends on the perceived risk of melanoma plus cosmetic and functional considerations.

Melanoma may arise in very large CNNs even in the first several years of life. Therefore, excision of very large CNNs should be considered as early as possible, but it is probably prudent to wait until after the first 6 months of life to reduce surgical and anesthetic risks. Management of patients with very large CNNs must be individualized. Extensive involvement of the body surface, with little or no normal skin available for graft sites, may necessitate abandoning efforts at prophylactic excision and accepting lifelong surveillance to detect the earliest signs of malignant change. It may be impossible to remove every nevomelanocyte in very large CNNs, particularly when there is involvement of vital structures or deep anatomic zones. The treatment goal is to remove as much of the nevus as possible while preserving function and improving cosmetic appearance. Other indications for surgical excision of very large CNNs include chronic pruritus, ulceration, and infection. Unlike surgical excision, dermabrasion and other modes of destructive therapy do not address the malignant potential of CNN; nevomelanocytes may still be left behind in the dermis, and the cosmetic results associated with destructive therapy are unpredictable. Melanoma has been reported after dermabrasion of large CNNs.17 “Pseudomelanoma” has been described after laser treatment of a giant CNN.18

The approach to small CNNs needs to be considered carefully. It appears that the risk of melanoma development depends on CNN size, and therefore, smaller lesions appear to have less risk. However, due to the smaller size, complete excision of small congenital nevi may be relatively straightforward, resulting in excellent cosmetic results. Although atypical-appearing CNNs should be considered for immediate excision, careful surveillance without excision may be an option for clinically benign lesions depending on gross appearance, size, location, cosmetic and functional deficits (or improvement) resulting from excision, and general health issues. Given the risk of general anesthesia, for lesions perceived to be at low risk during the first decade of life it is appropriate to consider waiting until the child is old enough to tolerate local anesthesia. All CNNs should be documented at birth, preferably in the form of high-quality photographs that can be used to aid follow-up by parents and physicians. Follow-up is complicated by the natural evolutionary changes that take place in a nevus during body growth (i.e., surface, size, color, and hair), and periodic updates of photographs may be warranted. Suspicious changes in color, surface, or size require urgent evaluation.

Prevention

There is no known preventive approach to avoid the development of congenital nevi. UV radiation (UVR)-induced mutations clearly play no role in the initial development of the lesions already present at birth. There are no current data on parental exposure that may give rise to congenital nevus formation in their offspring. The role of subsequent UVR exposure for secondary development of melanoma is unclear. However, it seems prudent to protect lesions from unnecessary UVR exposure.

Epidemiology

Nevus spilus occurs in less than 0.2% of newborns, 1% to 2% of white school children, and 2% of white adults.19 There are no prevalence data in darkly pigmented persons. There does not appear to be a gender predilection.19 When viewed as a risk marker for melanoma, nevus spilus shows a trend for being more common in melanoma cases than in controls. Kopf et al19 detected nevus spilus in 5 (4.8%) of 105 white adults with melanoma compared with 14 (2.3%) of 601 dermatology outpatients.

Etiology and Pathogenesis

Nevus spilus may be postulated to develop along similar pathways as a congenital nevus, but instead of the underlying mutation creating a massive accumulation of nevomelanocytic cells in the dermis, the genetic defect creates a field of cells that are susceptible to a secondary event leading to the development of focal individual melanocytic neoplasms within the localized melanocytic hyperplasia. The specific mutations, chromosomal aberrations (mosaicism), and/or dysregulated pathways involved in this process are unknown.

Clinical Findings

(Fig. 122-6)

History

Rarely, nevus spilus may be present at birth. More commonly, the lesion becomes evident during infancy or early childhood. More darkly pigmented, flat, or raised elements are usually present when the lesion is first recognized, but new pigmented elements may appear over time.

Cutaneous Lesions

Clinically, the lesion presents as a circumscribed macule/patch of tan pigmentation with features consistent with lentigo or café-au-lait macule including scattered, more darkly pigmented nevomelanocytic (or more hyperplastic) macular and/or papular elements. The tan macular background pigmentation ranges from less than 1 cm to greater than 10 cm in diameter (Fig. 122-7). Although nevus spilus may occur anywhere, lesions have been noted primarily on the torso and extremities. A divided nevus spilus of the eyelid has been reported.20 Lesions may be localized or have a segmental distribution. Giant varieties of nevus spilus may occur.

Related Physical Findings

Nevus spilus has been associated with other anomalies of vascular, central nervous system, or connective tissue origin. Multiple granular tumors and nevus flammeus have been associated with a giant nevus spilus. Large varieties of nevus spilus may be associated with muscle atrophy, other neurological disorders, and phacomatosis pigmentokeratotica.21

Laboratory Tests

Histopathology

The tan background pigmentation usually consists of increased numbers of melanocytes in a lentiginous epidermal pattern. Routine and electron microscopic studies of nevus spilus may demonstrate melanin macroglobules in some cases. The flat, dark elements of nevus spilus may demonstrate foci of increased melanocytic hyperplasia or melanocytic dysplasia (architectural disorder and variable cellular atypia), whereas the raised elements usually contain collections of nevomelanocytes in the epidermis and/or dermis. The neoplastic elements of nevus spilus may also consist of epithelioid and/or spindle cell nevi, nevi with dysplastic features, or blue nevi.

Special Tests

There are no identified molecular tests of value, at least currently.

Differential Diagnosis

(Box 122-2)

Complications

There are insufficient data to be certain of the natural history of nevus spilus or to comment specifically about its malignant potential; however, caution must be exercised in affected individuals. More than 20 cases of melanoma have been reported to develop in contiguity with nevus spilus, with some cases ending in metastatic disease and death.

Prognosis and Clinical Course

In general, nevus spilus is a benign lesion that may develop more spotted elements over time. Once developed, nevus spilus lesions are presumed to persist throughout life, although it is possible that some elements within the nevus spilus or even the entire nevus spilus itself could regress with time. There are no long-term follow-up studies of nevus spilus.

Treatment

No standard guidelines exist for the management of patients with nevus spilus. Clinical appearance (typical or atypical), history of stability or instability of pigmented elements, congenital or noncongenital onset, perceived risk of developing melanoma, and cosmetic concerns are considerations when determining whether to excise or recommend periodic clinical evaluation for life. Atypical-appearing new and/or unstable elements in nevus spilus should be evaluated by histopathologic examination to exclude melanoma. A nevus spilus with dysplastic or congenital features may have a greater risk of developing melanoma.22,23

Prevention

It is theoretically possible that increased UVR exposure results in the development of new nevomelanocytic proliferations or increased malignant potential of nevus spilus.

Epidemiology

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.

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.

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.

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

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.

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.

Etiology and Pathogenesis

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

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.

Clinical Findings

(Fig. 122-8)

History

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

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.

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).

Cutaneous Lesions

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.

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.

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.

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.

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.

Related Physical Findings

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.

Laboratory Tests

Histopathology

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.

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.

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.

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).

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

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).

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.

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.

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).

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.

No definitive and consistent histopathologic features have been described for eruptive nevi.

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

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.

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.

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.

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.

Special Tests

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.

Differential Diagnosis

(Box 122-3)

Complications

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.

Prognosis and Clinical Course

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.

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.

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.

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.

Treatment

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

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.

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.

Prevention

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.

Epidemiology

Blue nevi are present in fewer than 1 of 3,000 newborns, in approximately 1 of 1,000 children ≤5 years, in 1% to 2% of white school children, in 3% of Japanese adults, and in 0.5% to 4.0% of healthy white adults. The vast majority of blue nevi are single, small, deep-blue macules or papules approximately 1–3 mm in diameter.

Multiple blue nevi may be associated with lentigines, cardiac myxoma, and mucocutaneous myxomas [Carney complex/LAMB syndrome (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi)]. Blue nevi have been associated with nodular mastocytosis, and a histogenic relationship has been claimed for melanocytes and mast cells.61 Blue nevi have been reported to occur in oral mucosa, uterine cervix, vagina, spermatic cord, prostate, and lymph nodes.62

Etiology and Pathogenesis

The origin of common blue nevi and cellular blue nevi is unknown, but they may be derived from a mutant precursor cell resulting in the accumulation and differentiation of the melanocytic cells in the dermis instead of their normal location in the epidermis. Differentiation toward hair follicular melanocytes is possible. A specific mutation in the GNAQ gene has been identified in blue nevi.63 Some varieties of cellular blue nevi stain for CD34,64 suggesting a potential “stem cell” origin. Bednar's tumors (dermatofibrosarcoma protuberans including cells with melanocytic marker expression) also express CD34+ suggesting a similar stem cell origin for these tumors with different differentiation pathways.65 Nevus of Ito/Ota is related to common blue nevi but represents an extensive localized acquired proliferation. The extension of these neoplasms along specific neural pathways may provide insight into the etiology of these dermal proliferations, including the possible role of certain neural factors.

Clinical Findings

(Fig. 122-12)

History

Common blue nevi are usually acquired, and once developed should remain stable. Nevus of Ota and Ito may share similar underlying defects to blue nevi and are also often acquired (in early childhood, often before age 1 year or around puberty) but are far more extensive, encompassing a portion of trigeminal (ophthalmic and maxillary) and brachial (posterior supraclavicular and lateral cutaneous) nerve distributions, respectively. Dermal melanocytosis (Mongolian spot) may also be related to blue nevi but is usually present at birth or within the first few weeks of life and centered over the lumbosacral area. Lesions of dermal melanocytosis usually regress in early childhood but may persist in approximately 10% of cases.

Cutaneous Lesions

Common blue nevi are usually solitary, asymptomatic blue, blue–gray, or blue–black papules, usually less than 10 mm in diameter (Fig. 122-13). The blue–gray color of blue nevi is an optical effect of blue light backscatter from the skin over the dermal melanin (Tyndall effect). Hypopigmented, target or targetoid, and combined blue nevi (compound nevomelanocytic nevus and a blue nevus) also exist. Common blue nevi occur anywhere, but about half the reported cases present on the dorsa of hands and feet. Usually, the common blue nevus is singular, but rarely, lesions may be multiple and agminated or arranged in large plaques consisting of multiple solitary papules or nodules with intervening areas of blue discoloration. Common blue nevi also occasionally may have satellite lesions that may be mistaken for melanoma metastasis.66 Rare giant varieties of congenital blue nevus occur, often with multiple satellite lesions.9 The large plaque blue nevus (pilar neurocristic hamartoma) may occasionally be associated with a background of lentigo simplex.

The deep penetrating nevus may be considered a unique form of blue nevus, but some would include this lesion in the category of Spitz nevus. Deep penetrating nevi are darkly pigmented, blue–black papules or nodules, mostly on the head and neck or upper extremities, 2–9 mm in diameter, and occurring predominantly in the first four decades of life, including childhood.67

Cellular blue nevi are blue–gray or blue–brown nodules or plaques 1–3 cm in diameter, occasionally larger (see Fig. 122-13C). Their surface is usually smooth but may be irregular. Approximately one-half the cases are located on the buttocks or sacrum. Cellular blue nevi may develop in association with CNN, occasionally with target appearance. Cellular blue nevus differs from the common blue nevus in that it is usually larger, more elevated, more aggressive locally, and occasionally associated with lymph node “benign metastasis.” Complicating the picture is the fact that melanoma may develop in a cellular blue nevus.

Malignant blue nevus (melanoma) may develop in contiguity with a cellular blue nevus, nevus of Ota, combined congenital blue nevus, or de novo. Malignant blue nevus presents as an expanding dermal nodule with or without ulceration. There is some dispute as to whether malignant blue nevus should be considered a separate entity from melanoma or simply referred to as a melanoma developing in a blue nevus.

Related Physical Findings

The presence of epithelioid blue nevi may warrant consideration of Carney complex/myxoma syndrome/LAMB syndrome, with evaluation for related findings, including atrial myxomas and endocrine tumors.

Laboratory Tests

Histopathology

In common blue nevi, dermal melanocytes appear as melanin-containing fibroblast-like cells grouped in irregular bundles admixed with melanin-containing macrophages, associated with excessive fibrous tissue in the middle or upper reticular dermis, occasionally extending downward to subcutaneous fat or upward to papillary dermis (Fig. 122-14). Elongated melanin-producing dermal melanocytes in common blue nevi usually lie with their long axis parallel to the epidermis. Except in the case of combined blue nevus (with a compound nevomelanocytic nevus component), the epidermis in common blue nevi appears normal. Combined blue nevi have been noted in 1% of melanocytic nevi excised for histopathologic examination.68

Pathology of the plaque-like blue nevus (pilar neurocristic hamartoma) reveals a peripilar grouped arrangement of mostly spindle cells containing varying amounts of melanin, patterns of a common blue nevus and dermal melanocytosis (Mongolian spot), and presence of abnormal (granular) melanosomes. There are other varieties of plaque-like blue nevi with subcutaneous cellular nodules with a range of histologic appearances from dermal melanocytosis to common blue and cellular blue nevi.69

Deep penetrating nevus—identical or similar to plexiform spindle-cell nevus—may have both spindle and epithelioid cell forms and demonstrates deep extension into the dermis or subcutis in a wedge-shaped structure potentially tracking with neurovascular or adnexal structures.70 These lesions may be related to cellular blue nevi.

In cellular blue nevi, there is usually a component of a common blue nevus plus fascicles of spindle-shaped cells with ovoid nuclei and abundant pale cytoplasm with little or no melanin, and often epithelioid cells, present in the dermis and often in subcutaneous fat in nests, bundles, and neuroid forms with little or no intervening stroma (see Figs. 122-14C and 122-14D). Epithelioid cell and amelanotic varieties of the cellular blue nevus have been described. Epithelioid blue nevi have been reported in association with cardiac myxoma71 or in isolation.72 Histopathologic diagnosis may be difficult when the common blue nevus component and melanin production are sparse or inapparent. Differentiation of some cellular blue nevi from melanoma can be difficult. Occasionally, small groups of well-differentiated melanocytes are present in the marginal sinus or parenchyma of lymph nodes draining the anatomic site of the cellular blue nevus, making it difficult to differentiate malignant metastasis from benign “metastasis”. It is likely that “inert” deposits of melanocytes in the capsules and peripheral sinuses of lymph nodes draining some varieties of cellular blue nevus are transported passively (see Section “Nodal Nevi”).

The malignant blue nevus is a variant of melanoma, distinguished from cellular blue nevus by invasiveness, cellular atypia, pleomorphism, atypical mitoses, and areas of necrosis.

Special Tests

Imaging tests of the heart may be required if there is concern for Carney complex/myxoma syndrome/LAMB syndrome.

Differential Diagnosis

(Box 122-4)

Complications

A major complication of blue nevi is the potential risk of melanoma. This risk appears to be highest for cellular blue nevi. Melanoma has been noted to evolve in large blue nevus patches or plaques and in associated with nevus of Ota and Ito.

Prognosis and Clinical Course

The natural evolution has not been studied for common blue nevi or cellular blue nevi. It is likely that once established, blue nevi remain unchanged or possibly regress over time. “Change” is worrisome for melanoma development.

Treatment

A common blue nevus that is stable for many years in an adult usually requires no therapy. Sudden appearance of a blue nodule, expansion of a preexisting blue nodule, a congenital blue nodule, or a relatively large blue nodule or plaque greater than 10 mm in diameter should be considered for histopathologic examination. Excision should include subcutaneous fat to ensure complete removal of deep dermal melanocytes, which are frequently present in the subcutaneous tissue of cellular blue nevus. The large plaque blue nevus (pilar neurocristic hamartoma) requires consideration for excision or periodic evaluation for suspicious change. Cellular blue nevus should be evaluated for excision because of its malignant potential.

Prevention

Sun exposure has been implicated as a causative factor in eruptive blue nevi.73 Thus, as with other nevi, it is reasonable to minimize excessive UVR exposure.

Epidemiology

The mean age of presentation has been reported as 25.3 years, ranging from 2.5 to 56.0 years of age.74 Similar age ranges have been reported in other studies.75 The majority of cases occur in the third decade of life. Female patients outnumber male patients with reported ratios of 2:1,74 1.4:1.0,75 and 1.3:1.0.76 The majority of these lesions are found on the extremities with reported frequencies of 67.0%,74 69.6%,76 and 75.0%.75 There is a preference for the lower extremity, especially the thigh, with the back being the next most common site.75

Etiology and Pathogenesis

It may be presumed that PSCN are derived from the same progenitor cells giving rise to epidermal melanocytes and nevomelanocytes. No known specific mutation has been identified.

Clinical Findings

(Fig. 122-15)

History

PSCN was first described by Reed in 1975.77 These lesions are generally detected as acquired lesions, often during the third decade of life. At presentation, patients often note that the lesion has increased in size.75,76 It is not known how quickly these lesions grow, but growth may be relatively rapid as one case report of a lesion on a 3-year-old child documented significant growth over a 3 to 6 month period.78 Once fully developed, it is assumed that these lesions will remain stable, but the full natural history of these lesions is not well characterized.

Cutaneous Lesions

The PSCN is usually a sharply circumscribed, uniformly darkly pigmented papule74–76 (Fig. 122-16). Dermoscopically, most of the lesions are jet black but may be blue–gray or brown. In the initial growth phase, the lesions may have a globular appearance78 but the vast majority of these lesions are uniformly dark, with a sharp interface with surrounding skin often exhibiting streaks/pseudopods and giving the lesion a starburst appearance.

Related Physical Findings

No known association.

Laboratory Tests

Histopathology

PSCN consists of vertically oriented fascicles of spindle-shaped, pigment-producing melanocytes (Fig. 122-17); some pagetoid upward migration may be present, but the lesion can be distinguished from melanoma by uniform nuclei, uniform cellular detail, and distinctive pattern of growth. Almost all cases of pigmented spindle cell nevus have a lymphohistiocytic host response. Spindle cells extend down eccrine ducts in 40% and involve hair follicles in 22% of lesions.74 There is an overlap of these lesions with epithelioid cell and spindle cell nevi (Spitz tumor). In a review of 91 PSCN by Sagebiel et al,74 cells were predominantly spindle in 74% and mixed spindle cell and epithelioid cell in 26% of patients. There are atypical variants of PSCN in which there are architectural alterations and striking cellular atypia.76

Special Tests

Although BRAF mutations have been noted, these mutations are also present in other acquired nevi, and thus far there is no specific marker for PSCN.

Differential Diagnosis

(Box 122-5)

Complications

There are no reported complications, but misinterpretation of benign or malignant behavior of the lesion could result in unnecessary or insufficient treatment, respectively.

Prognosis and Clinical Course

The PSCN are thought to be benign. No local recurrence or distant spread was noted for 38 patients followed for an average of 14 months.74 In another study, 57 patients were followed for an average of 6 years and again no local recurrence or metastasis was noted.75

Treatment

Given the frequent difficulties in the histopathological differentiation from melanoma, these lesions should be excised with 3–5 mm margins of normal skin.

Prevention

The role of UVR exposure in the development of PSCN is unknown.

Epidemiology

An annual incidence rate of 1.4 cases of Spitz nevus per 100,000 individuals has been estimated in Australia, compared with 25.4 per 100,000 individuals for cutaneous melanoma during the same time interval.79 Among melanocytic nevi excised in children, 1% to 8% of cases are interpreted as Spitz nevus.80 In a case series of 308 patients with Spitz nevi reported by Allen,81 15% of lesions occurred in adolescents and adults, the oldest patient being 56 years of age. There appears to be no gender predilection for Spitz nevus. Published cases have been described primarily in whites.

Etiology and Pathogenesis

It may be presumed that Spitz nevi are derived from the same progenitor cells that give rise to epidermal melanocytes and nevomelanocytes. Unlike common acquired nevi and congenital nevi, the B-RAF mutation does not appear to be involved. Amplifications of chromosome 11p and H-RAS and activating mutations of H-RAS have been noted in a subset of Spitz nevi.82 Heritable genetic factors have not been investigated systematically, but there is a single report of multiple nevi in identical twin boys.80 The role of trauma in the histogenesis of Spitz nevi is speculative. One case has been reported at the site of Bacille Calmette-Guérin vaccination.83

Clinical Findings

(Fig. 122-18)

History

The rate of growth, period of stabilization, and rate of regression of Spitz nevi are not known. The duration of solitary Spitz nevus before presentation is usually less than 9 months. Lesions usually show an increase in radial size over time, some gradual and others rapid.84 Based on patients with eruptive Spitz nevi, regression has been reported to occur and may even occur in some lesions while new lesions are appearing.85

Cutaneous Lesions

The most common variety of Spitz nevus is solitary, asymptomatic, pink or red, hairless, firm, and dome-shaped (Fig. 122-19). Some Spitz nevi may resemble a keloid. The surface is commonly smooth, and the borders may fade into surrounding skin. Verrucous, scaly, stippled, crusted, or (rarely) eroded lesions have been noted. Spitz nevi are usually asymptomatic, but pruritus, tenderness, and/or bleeding may occur.80 A halo of depigmentation has been associated with several cases of Spitz nevus.30,86 Spitz nevi are part of a spectrum in which some also include PSCN and deep penetrating nevi.

Spitz nevi can also present as widespread eruptive lesions or in a grouped manner as multiple agminated lesions consisting of red, red–brown, brown, or dark-brown papules or nodules, with a fine stippled surface (see Fig. 122-19C). Agminated Spitz nevi often occur in the early years of life within a background of congenital (sometimes acquired) macular pigmentation (nevus spilus) or occasionally within a hypopigmented plaque. Spitz nevi may also develop as single or multiple lesions in a large CNN.

The diameter of Spitz nevi ranges from several millimeters to several centimeters, the average being 8 mm in one series.80 In 73% of patients in one series,79 the nevus diameter was 6 mm or less, and in 94% of patients, the nevus diameter was less than 10 mm. Most cases are described as superficial papules or nodules, although subcutaneous involvement may occur.85 In one series of 43 patients,80 the anatomic location included the head or neck in 18, upper extremities in 9, torso in 9, and lower extremities in 7. Spitz nevi tend to spare palms, soles, and mucous membranes.

Related Physical Findings

There is no known association with other somatic abnormalities.

Laboratory Tests

Histopathology

Unlike ordinary nevi and melanomas, melanocytic cells in Spitz nevi are large—often twice the size of epidermal basal keratinocytes,84 with prominent mononuclear or multinucleated giant cells in the epidermis and/or dermis (Fig. 122-20). Mitoses, usually few in number, are detected in one-half the cases,86 whereas atypical mitoses are uncommon in Spitz nevi. In contrast to melanoma, the melanocytic cells in Spitz nevi show progressive maturation with increasing depth, becoming smaller and more similar to ordinary nevomelanocytes,84,86 with the overall distribution of cells in the dermis being wedge-shaped, with narrowing of the wedge toward the subcutaneous fat.

Coalescent eosinophilic globules (Kamino bodies), periodic acid-Schiff-positive and diastase-resistant (resembling colloid bodies), have been reported in 60% of Spitz nevi87 (see Fig. 122-20). Similar globules may be detected in 2% of melanomas and 0.9% of typical acquired nevi, but the globules are smaller in size, more difficult to find, single rather than coalescent, and commonly periodic acid-Schiff-negative.87

Melanocytic elements are usually arranged in well-circumscribed nests, although there may be permeation of the epidermis by single cells or small groups of cells. In those cases with epidermal nests, artifactual clefts are usually seen above the nests in half the cases, a finding rarely observed in melanoma.79 The epidermis is usually hyperplastic, with elongated and bulbous pegs and knobs extending into the dermis, although thinning and even ulceration may occur rarely. The dermal inflammatory cell infiltrate may be slight or marked, band-like, and mainly at the base or patchy around blood vessels and/or intermixing with nevus cells. Although melanin was observed in all 13 patients originally described by Spitz,84 more recent studies have determined that melanin was moderate in 10% of cases and heavy in 5%.86

Although the bizarre histopathologic features and frequent occurrence of dermal inflammation may cause diagnostic confusion, Spitz nevus usually can be differentiated from melanoma. The histologic features of Spitz nevus in children and adults are similar.

Special Tests

A subgroup of Spitz nevi have a gain of chromosome 11p and amplification or activation of H-RAS.82 These markers are not routinely used in the clinical setting but may be helpful in the future for discriminating these nevi from other melanocytic neoplasias. Retention of p16 may also help discriminate Spitz nevi from Spizoid melanomas.88

Differential Diagnosis

(Box 122-6)

Complications

Misinterpretation of benign or malignant behavior of the lesion could result in unnecessary or insufficient treatment, respectively.

Prognosis and Clinical Course

The natural history of the Spitz nevus is largely unknown. Based on patients with eruptive Spitz nevi, it is clear that spontaneous regression can occur.85 A concern is that some lesions diagnosed as Spitz nevi may progress to melanoma or represent melanoma at the outset.89

Treatment

Complete excision with a 3–5 mm clear margin of normal skin is generally sufficient treatment for Spitz nevi. Given the difficulty of confidently excluding the possibility of melanoma in certain cases, an even wider margin of normal skin may be prudent for histopathologically worrisome lesions.89 Incompletely excised lesions may recur in as many as 7% to 16% of patients.80,90–92 Although some authors have advocated sentinel node biopsies in these lesions, this may only add to the confusion because Spitz nevus cells may be present in the regional lymph nodes but not necessarily indicate malignancy.93 Management of patients who have numerous Spitz nevi requires individual judgment and periodic surveillance for new or unstable lesions.

Prevention

The role of UVR exposure in the development or progression of Spitz nevi is unknown.

Epidemiology

Nevomelanocytes can be identified in lymph nodes with a frequency ranging from 0.3% to 7.3% in lymphadenectomies not related to melanoma and up to 22% in regional nodes removed because of melanoma.94 When nevomelanocytes are evident in lymphadenectomies due to melanoma, it has been reported that 75% of the primary cutaneous melanomas had an associated nevomelanocytic nevus, often with congenital features.95 A significant association has also been noted for the presence of cutaneous nevomelanocytic nevi in the zones of skin drained by lymph nodes that were found to include nevomelanocytes.96 In most cases, the nevomelanocytes appear to be derived from common acquired nevomelanocytic nevi, but CNNs, blue nevi, cellular blue, and Spitz nevi have all also been reported to involve regional lymph nodes.62

Etiology and Pathogenesis

There are two prevailing theories as to the mechanism by which nevomelanocytes appear in regional lymph nodes.

The first theory is that during development, nevomelanocytes get trapped in developing nodal tissues. Some support for this theory could be based on the fact that nodal nevi can be found in association with CNNs. This observation suggests that there is an opportunity for nevomelanocytes to be deposited during development. Further, blue nevus cells can be found in tissues such as prostate, cervix, vagina, spermatic cord, and seminal vesicles.62 Thus, aberrant migration and differentiation of melanocytic cells does occur.

The second theory suggests that there may be passive transfer from the cutaneous lesion to the lymph node. Substances such as carbon, tattoo ink, and radioactive colloid are readily transferred to the draining lymph node. It is reasonable to assume that loosely adherent nevomelanocytes could also traverse the same path. In fact, nevomelanocytes have been noted in lymph channels.62 Once in the lymph node, nevomelanocytes are generally identified in the capsule, but they can also be found in the parenchyma.94 It is not known how nevomelanocytes get into the capsule, but it is reasonable to assume that these cells migrate from the parenchyma into the capsule. It is important to note that melanoma cells can also be found in the capsule,97 so it is rational to assume that entry into the capsule is not limited to a developmental event. The fact that nevomelanocytes in regional lymph nodes are highly correlated with the presence of nevomelanocytic nevi in the skin supports the concept that these cells may arrive in lymph nodes via dissemination from benign cutaneous lesions.

Clinical Findings

(Fig. 122-21)

History

Generally, nodal nevi are identified in lymph nodes that are removed because of melanoma, but these benign cells are also identified in nodes removed for other reasons. Generally, the patient does not note symptoms related to nodal nevi.

Cutaneous Lesions

Common acquired nevomelanocytic nevi, CNNs, blue nevi, and Spitz nevi have been associated with nodal nevi.62

Related Physical Findings

Due to concern for melanoma, patients should be evaluated for findings that might be worrisome for metastatic melanoma.

Laboratory Tests

Histopathology

Pathology often reveals nevomelanocytes largely confined to the nodal capsule. However, cells may also be noted in the parenchyma. These cells should bear resemblance to the cells in the cutaneous lesion. Lack of proliferative markers (Ki67) and possibly high levels of p16 immunohistochemical markers support a benign diagnosis.98

Special Tests

The use of standard immunohistochemical tests may help identify the location and cellular features of nevomelanocytes in lymph node tissue sections. Reverse transcriptase–polymerase chain reaction tests for tyrosinase mRNA in lymph nodes do not discriminate benign from malignant melanocytic nodal disease.

Differential Diagnosis

(Box 122-7)

Complications

Complications, such as scarring or lymphedema, may be the consequence of lymphadenectomy. Misinterpretation of benign nodal deposits as malignant could result in unnecessary regional lymph node dissection and treatment with systemic agents. Misinterpretation of malignant melanocytes as benign in lymph nodes may lead to undertreatment.

Prognosis and Clinical Course

If the lymph node deposits are determined to be benign, no further treatment is warranted.

Treatment

None required for benign nodal nevi.

Epidemiology

The frequency of lentigo simplex in children and adults has not been determined. There does not appear to be a racial or gender predilection. Lentigo simplex is the most common histopathologic pattern of darkly pigmented lesions excised from acral sites of persons who have darkly pigmented skin.29 Pigmented nail bands, noted in up to 20% of Japanese, may have histopathologic features of lentigo simplex.99 For agminated lentigines, the population prevalence is unknown but believed to be rare.

Etiology and Pathogenesis

The increased density of melanocytes in lentigines is presumably due to an underlying developmental or intrinsic defect in melanocyte homeostasis. In some lentigines, the presence of melanin macroglobules in melanocytes and keratinocytes suggests that defects affecting melanization pathways are also involved. The presence of lentigo simplex in association with somatic abnormalities in such diverse conditions as Peutz–Jeghers syndrome, LEOPARD syndrome (lentigines; electrocardiogram conduction defects; ocular hypertelorism; pulmonary stenosis; abnormalities of genitalia; retardation of growth, and sensorineural deafness), and LAMB/myxoma syndrome suggests that lentigo development may be influenced by a number of different developmental and genetic factors. For agminated lentigines, it is possible that chromosomal mosaicism plays a role in the development of the localized grouping of lentigines. The cause for delayed appearance of lentigines in the skin, mucosa, and nail matrix in Laugier–Hunziker pigmentation is unknown.

Clinical Findings

(Fig. 122-22)

History

Unlike solar lentigines, lentigo simplex is by definition UVR independent. Lentigo simplex may appear as early as the first decade and may occur anywhere on skin or mucous membranes.

Generalized lentigines may occur as an isolated phenomenon without known familial aggregation and first appear at birth, during infancy, or during adulthood. Familial clustering in an autosomal dominant pattern has been noted. A number of syndromes are recognized (see Chapter 75).

In Moynahan (LEOPARD) syndrome, lentigines are present at birth or shortly thereafter and may increase in number during childhood. In Peutz–Jeghers syndrome, numerous lentigines may be present at birth or appear during early childhood. Oral pigmentation usually persists in Peutz–Jeghers syndrome, whereas cutaneous lentigines usually fade after puberty. In LAMB syndrome, the lentigines on the lips and genital sites appear in early childhood and tend to persist. In Laugier–Hunziker pigmentation, lentigines are acquired during adulthood and persist indefinitely, not associated with somatic abnormalities. Agminated lentigines first become manifest at birth or early childhood.

Cutaneous Lesions

Lentigo simplex usually is a sharply circumscribed, light-brown to very dark-brown macule.

In Moynahan (LEOPARD) syndrome, lentigines occur on both sun-exposed and sun-protected sites, including genitalia, conjunctiva, oral mucosa, palms, and soles. In Peutz–Jeghers syndrome, lentigines are almost always present on the oral mucosa. Other common sites of involvement include lips, nose, eyelids, anus, nail bed, and dorsal and ventral surfaces of hands and feet.

Lentigines in the myxoma syndrome (LAMB) occur mainly on the face and genitalia as tan to black macules (Fig. 122-23). In centrofacial lentiginosis, the presence of pigmented macules is restricted to a horizontal band across the central face. Lentigines in Laugier–Hunziker pigmentation occur on the buccal and labial mucosa of the mouth, on fingertips and nail matrix, and occasionally in other sites of the skin and mucous membranes.

Agminated lentigines first become manifest at birth or early childhood as small, circumscribed, light-brown macules, 2–10 mm in diameter, confined to a localized area of the skin, often in a segmental distribution (Fig. 122-24) and frequently in a curvilinear or swirled pattern. Wood's lamp examination may be required to differentiate agminated lentigines from nevus spilus, because the macular background pigmentation is evident in the latter and absent in the former.

Related Physical Findings

If there is concern that the lentigines are part of a syndrome, further evaluation is appropriate, and should be guided by the physical findings and syndrome under consideration.

Laboratory Tests

Histopathology

Lentigo simplex consists of intraepidermal melanocytic hyperplasia in the basal layer of elongated epidermal rete ridges, without nest formation. At one end of the lentigo spectrum, lesions are more similar to café-au-lait lesions, in which the melanocyte number may only be minimally increased but pigmentary differences are marked; at the other end of the spectrum, the number of melanocytes is sufficiently increased to begin forming nests, appearing similar to a junctional nevus. Depending on the degree of keratinocytic hyperplasia, distinct separation from solar lentigo may not be possible based on histopathologic interpretation alone. Giant pigment granules (melanin macroglobules) may occur in lentigo simplex in isolation, and in association with multiple-lentigines (LEOPARD) syndrome.

In agminated lentigines and Laugier–Hunziker pigmentation, histopathologic studies reveal increased numbers of melanocytes in elongated epidermal rete ridges, similar to lentigo simplex, without nests of nevomelanocytes or cellular inflammation.

Special Tests

Mart-1, Mel-5, and DOPA histochemistry may be useful to demonstrate increased number of melanocytes confined to the basal layer and lacking junctional nest formation. If a syndrome is under consideration, imaging studies may be required and genetic testing may be considered.

Differential Diagnosis

(Box 122-8)

Complications

There are no known complications from lentigo simplex. Complications arise from the associated syndromes. Atypical varieties of lentigo simplex (in any anatomic site) may be potential precursors or masqueraders of melanoma.

Prognosis and Clinical Course

The natural history of isolated lentigo simplex is not known. Once developed, lesions are presumed to be relatively stable. There is no convincing evidence that lentigo simplex evolves to a nevomelanocytic nevus. As with any process in which melanocytes are present (including normal skin), it is possible for melanoma to arise in a lentigo, but an elevated risk has not been demonstrated conclusively for lentigo simplex.

The long-term course and malignant potential of agminated lentigines and the lentigines in Laugier–Hunziker pigmentation are unknown.

Treatment

There is no need to treat benign-appearing lentigo simplex. Cosmetic removal may be achieved with cryotherapy or other destructive approaches such as Q-switched laser. There is a theoretical risk of malignant transformation of any variety of melanocytic hyperplasia or dysplasia using any type of laser. Caution must be exercised to ensure the lesion being treated using destructive therapy is benign. Lesions that are significantly unusual, irregular, asymmetric, or changing in shape should be examined histopathologically to exclude melanoma before destructive therapy is considered. Wood's lamp examination is useful in defining margins of lentigo simplex.

Until the long-term course of agminated lentigines and Laugier–Hunziker pigmentation is known, it may be prudent to recommend periodic examinations to detect the earliest signs of possible malignant evolution.

Prevention

UVR is clearly associated with the development of solar lentigines, but its role in the different types of simple lentigines is not known. However, it is rational to limit UVR overexposure.

Epidemiology

The prevalence of solar lentigines is correlated directly with increasing age, and they are present in 90% of white people over 60 years of age.101 Solar lentigines are common in individuals who sunburn easily and do not tan, whereas they are uncommon among people who have darkly pigmented skin.102

Lentigines may be induced by photochemotherapy [psoralen and UVA light (PUVA) lentigo], occurring in 40% to 50% of patients an average of 5.7 years after starting therapy, their frequency and severity directly attributable to the total number of treatments (Fig. 122-25).102 Darkly pigmented skin is associated with the lowest risk for PUVA-induced or solar-induced lentigines.102 Lentigines have been associated with UVA tanning bed use.103

Lesions similar in gross and microscopic appearance to solar lentigo, freckle (ephelis), may occur in children and young adults.100 They may appear within the first 5 years of life, tend to aggregate in families, and are significantly associated with red hair; their location and density correlate with sun sensitivity and sun exposure. The presence of freckles has been associated with a 2.5-fold increase in the rate of sunburn susceptibility and poor tanning response and a threefold greater likelihood of a lower minimal erythema dose in people who mostly burn and tan minimally or not at all.104 The presence of dense sun-induced freckling increases the estimated risk for melanoma by three- to fourfold.105

Etiology and Pathogenesis

Solar lentigines are thought to represent a marker of intermittent high-intensity UVR, cumulative UVR, and/or a unique susceptibility to the proliferative, stimulatory, and/or mutagenic effects of UVR. Given the hyperplasia of both the keratinocytes and melanocytes, the primary defect in solar lentigines could be in either cell type eliciting a secondary proliferative response in the other.

There is a pronounced link between UVR exposure and the development of lentigines. Single exposures of experimental UVB radiation (320 mm) that is six to ten times the minimal erythema dose induces “freckling” in susceptible individuals.106 Phototoxic doses of PUVA may lead to the development of lentigines 6–8 months later.107 In addition to the total dose of UVR received during photochemotherapy, individual susceptibility factors to lentigo development include degree of skin pigmentation, ethnicity, age, and burning/tanning response to sunlight.102

Supportive of the underlying mutation being present in the melanocytes is the finding that epidermal melanocytic cellular atypia persists in lentigines developing in patients receiving chronic photochemotherapy for 1–2 years or longer after therapy is discontinued.102 In xeroderma pigmentosum (XP), in which patients have an increased sensitivity to UVR, hyperpigmented macules develop on light-exposed skin within the first 5 years of life (see Chapter 139), and these lesions demonstrate hyperplasia of variably atypical epidermal melanocytes (i.e., atypical lentigines). In one series of XP patients from Japan,108 lentigo maligna melanoma was the predominant melanoma type, suggesting an association between this tumor subtype, sensitivity to UVR, and the presence of UVR-induced atypical solar lentigines, and supportive of the underlying mutation being in the melanocytic lineage.

Clinical Findings

(Fig. 122-26)

History

Solar lentigines appear as acquired lesions, generally in fair-skinned individuals, on sun-exposed skin surfaces. For the majority of solar lentigines, it is assumed that once present, they persist indefinitely.

Cutaneous Lesions

Solar lentigo occurs as a pigmented macule on skin exposed to natural sunlight or artificial sources of UVR, usually in the presence of similar lesions in the same location (Fig. 122-27). Lesions may be tiny (<1 mm in diameter) or large (up to a few centimeters in diameter), with a tendency to confluence in severely sun-damaged skin and with smooth or irregular outlines. Lesions are usually light brown, but varieties of solar lentigo are jet black, similar to an India ink stain (ink spot lentigo). Although solar lentigo usually occurs on sun-exposed skin, identical-appearing lesions may occur on sun-protected sites (including the penis and buttocks) that have been exposed to photochemotherapy (see Fig. 122-25). When examined by dermoscopy, solar lentigines reveal a uniform reticular network.109 Lentigines in patients receiving PUVA and in individuals who have XP are often darkly and/or irregularly pigmented. Solar lentigines not apparent in visible light may be visualized using Wood's lamp illumination.

The oral–labial melanotic macule has gross morphologic characteristics similar to solar lentigo (Fig. 122-28), but its relation to a sun-sensitive phenotype or excessive sun exposure has not been well documented.

A clinical distinction has been made between a freckle (ephelis) and a solar lentigo. Freckles are common on the central face and often first noted in early childhood, presumably developing after significant sun exposure and are said to fade or even disappear when sun exposure is discontinued. Unfortunately, there are no longitudinal studies of ephelides or solar lentigines that document gross morphologic or time-course differences that would reliably allow a clinical distinction between ephelides and solar lentigines. According to l-3,4-dihydroxyphenylalanine (DOPA) studies on epidermal sheets, ephelides have been reported to show increased melanogenesis but decreased melanocyte number, which implies a different pathologic basis.106,110 However, counting melanocytes in DOPA-incubated epidermal sheets is unreliable for pigmented lesions, and these early studies must be questioned. Studies in DOPA-incubated tissue vertical sections demonstrate that melanocytes are increased in “ephelides” in children and young adults, similar to solar lentigines.42,109

Related Physical Findings

Patients with solar lentigines are more likely to be fair skinned, particularly those with red hair and or lighter eye color. Along with the lentigines, increased solar damage may be noted, and other lesions such as idiopathic guttate hypomelanosis, actinic keratoses, and seborrheic keratoses may be present. The presence of solar lentigines is a risk factor for melanoma, basal cell cancer, and squamous cell cancer.

Laboratory Tests

Histopathology

Solar lentigines reveal elongated epidermal rete ridges with club-shaped or bud-like extensions, frequent branching and fusing of rete ridges, a thinned or atrophic epidermis between rete ridges, and increased numbers of epidermal melanocytes without nesting. The microscopic appearance suggests a concurrent proliferation of keratinocytes and melanocytes.111 There is a scant to moderate perivascular mononuclear cell infiltrate in the dermis, usually associated with scattered melanin-laden macrophages.

Electron microscopic studies of solar lentigo reveal abundant melanosome complexes in keratinocytes, the complexes being generally larger than complexes in keratinocytes in adjacent skin.111 Compared with melanocytes in sun-protected skin, melanocytes in solar lentigo reveal increased activity manifested by marked DOPA reactivity (suggesting increased tyrosinase activity), elongated dendrites, large numbers of normal-appearing melanosomes, enlarged perikarya with well-developed rough endoplasmic reticula, numerous mitochondria, and hypertrophic Golgi complexes.112 Melanin macroglobules have also been noted.100

Pathologic features of PUVA-induced lentigo include increased numbers of melanocytes in elongated epidermal rete ridges, with large cell bodies and sometimes atypical cellular morphologic features, dendrites often extending high into the epidermis, and melanocytes frequently residing above the epidermal basal unit.109 Melanocytes in PUVA lentigo occasionally manifest autophagocytosis, sharply invaginated nuclear contours, nuclear pseudoinclusions, double nuclei, striking melanosomal alterations, and melanin macroglobules; melanosomes in keratinocytes of PUVA lentigines are often large and single instead of small and compound as in solar lentigines.112 Cosmetic UVA tanning also induces lentigines, and cellular atypia has been reported.

Histopathologic characteristics of the labial melanotic macule (labial lentigo) are similar to those of solar lentigo, showing melanocytic hyperplasia but without cellular atypia. The presence of melanocytic hyperplasia in labial melanotic macule is not a uniform finding in all studies.

Special Tests

Mart-1 and DOPA histochemical studies may be useful to demonstrate increased number of melanocytes confined to the basal layer and a lack of junctional nest formation.

Differential Diagnosis

(Box 122-9)

Complications

A potential complication is the discovery that an atypical solar lentigo is actually melanoma (often of the lentigo maligna variety).

Prognosis and Clinical Course

Solar lentigines may appear at any time of life. A solar lentigo may enlarge, darken, and become stable over time, but longitudinal studies of solar lentigines are lacking. It is possible that once formed, solar lentigines may persist indefinitely or fade slightly with time if UVR is avoided. Solar lentigines may be a heterogeneous population that includes lesions that fade and lesions that do not fade after UVR avoidance. The presence of these lesions suggests an increased risk for melanoma and keratinocytic skin cancers.

It has been proposed that some varieties of lichenoid keratosis may be due to an acute inflammatory reaction targeting the solar lentigo, and that resolution of lichenoid keratosis may cause regression of the associated lentigo.113 This speculation has not been substantiated.

The long-term course of atypical varieties of PUVA lentigo is unknown, but it is clear that PUVA lentigines (see Fig. 122-25) may persist 1–2 years or longer after therapy is discontinued102 and that cellular atypia of epidermal melanocytes in these lesions may persist as well. It is also clear that these patients may be at increased risk for melanoma114 and should be followed periodically for life.

Lentigo maligna (see Chapter 124) may masquerade as a solar lentigo early in its development or, alternatively, may evolve from a preexisting solar lentigo. A solar lentigo not matching the patient's other lentigines and/or enlarging/darkening out of step should be examined histopathologically or followed closely.

Treatment

Solar lentigo usually requires no therapy, but importantly, its presence indicates sensitivity and/or excessive exposure to UVR. Bleaching creams containing hydroquinone are usually not effective. Cryotherapy or other superficial destructive techniques (such as Q-switched laser) may be an option if the lesion is clearly benign, but lesions may recur after therapy. There is a theoretical concern about intense light treatment (i.e., laser) of any melanocytic hyperplasia or dysplasia.

Prevention

It may be possible to prevent further UVR-induced lentigines by reducing or avoiding UVR exposure. Ideally, protection against overexposure to UVR should be initiated during early childhood and continued throughout life. Vitamin D supplementation needs to be considered for patients practicing UVR protection and avoidance.